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Mastoor Y, Murphy E, Roman B. Mechanisms of postischemic cardiac death and protection following myocardial injury. J Clin Invest 2025; 135:e184134. [PMID: 39744953 DOI: 10.1172/jci184134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a "drug cocktail" approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.
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Xiao Z, Li S, Wu X, Chen X, Yan D, He J. GATA-4 overexpressing BMSC-derived exosomes suppress H/R-induced cardiomyocyte ferroptosis. iScience 2024; 27:110784. [PMID: 39391723 PMCID: PMC11466636 DOI: 10.1016/j.isci.2024.110784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 07/01/2024] [Accepted: 08/19/2024] [Indexed: 10/12/2024] Open
Abstract
Bone marrow mesenchymal stem cell (BMSC)-derived exosomes overexpressing GATA-4 (Exosoe-GATA-4) can protect cardiac function. Mitochondrial permeability transition pore (mPTP) has a crucial role in ferroptosis. This study aimed to assess the mechanism of Exosoe-GATA-4 in myocardial ischemia/reperfusion (I/R) injury. Exos were successfully excreted, and 185 differential expression miRNAs were obtained using bioinformatics. The Exosoe-GATA-4 effectively suppressed hypoxia/reoxygenation (H/R)-induced cardiomyocytes' ferroptosis, while the effects were reversed by miR-330-3p inhibitor. miR-330-3p targeted negative regulated BAP1. The effects of miR-330-3p inhibitor were reversed by knock-down BAP1. Also, BAP1 reversed the effects of Exosoe-GATA-4 on H/R-induced cardiomyocytes' ferroptosis by downregulating SLC7A11. Mechanistically, BAP1 interacted with IP3R and increased cardiomyocytes' Ca2+ level, causing mPTP opening and mitochondrial dysfunction, promoting H/R-induced cardiomyocytes' ferroptosis. Moreover, hydrogen sulfide (H2S) content was increased and regulated the keap1/Nrf2 signaling pathway by Exosoe-GATA-4 treated. Exosoe-GATA-4 effectively suppresses H/R-induced cardiomyocytes' ferroptosis by upregulating miR-330-3p, which regulates the BAP1/SLC7A11/IP3R axis and inhibits mPTP opening.
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Affiliation(s)
- Zhiyuan Xiao
- Department of Medical Intensive Care Unit, the First People′s Hospital of Yunnan Province, No.157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Si Li
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650500, P.R. China
| | - Xinxin Wu
- Yunnan University of Traditional Chinese Medicine, No.1076 Yuhua Road, Kunming, Yunnan 650500, China
| | - Xinhao Chen
- The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650500, P.R. China
| | - Dan Yan
- Department of Medical Intensive Care Unit, the First People′s Hospital of Yunnan Province, No.157 Jinbi Road, Kunming, Yunnan 650032, China
| | - Jigang He
- Department of Cardiovascular Surgery, the First People′s Hospital of Yunnan Province, No.157 Jinbi Road, Kunming, Yunnan 650032, China
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Sigle M, Rohlfing AK, Cruz Santos M, Kopp T, Krutzke K, Gidlund V, Kollotzek F, Marzi J, von Ungern-Sternberg S, Poso A, Heikenwälder M, Schenke-Layland K, Seizer P, Möllmann J, Marx N, Feil R, Feil S, Lukowski R, Borst O, Schäffer TE, Müller KAL, Gawaz MP, Heinzmann D. Targeting Cyclophilin A in the Cardiac Microenvironment Preserves Heart Function and Structure in Failing Hearts. Circ Res 2024; 135:758-773. [PMID: 39140165 DOI: 10.1161/circresaha.124.324812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 08/01/2024] [Accepted: 08/07/2024] [Indexed: 08/15/2024]
Abstract
BACKGROUND Cardiac hypertrophy is characterized by remodeling of the myocardium, which involves alterations in the ECM (extracellular matrix) and cardiomyocyte structure. These alterations critically contribute to impaired contractility and relaxation, ultimately leading to heart failure. Emerging evidence implicates that extracellular signaling molecules are critically involved in the pathogenesis of cardiac hypertrophy and remodeling. The immunophilin CyPA (cyclophilin A) has been identified as a potential culprit. In this study, we aimed to unravel the interplay between eCyPA (extracellular CyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function. METHODS Employing a multidisciplinary approach encompassing in silico, in vitro, in vivo, and ex vivo experiments we studied a mouse model of cardiac hypertrophy and human heart specimen to decipher the interaction of CyPA and the cardiac microenvironment in highly relevant pre-/clinical settings. Myocardial expression of CyPA (immunohistology) and the inflammatory transcriptome (NanoString) was analyzed in human cardiac tissue derived from patients with nonischemic, noninflammatory congestive heart failure (n=187). These analyses were paralleled by a mouse model of Ang (angiotensin) II-induced heart failure, which was assessed by functional (echocardiography), structural (immunohistology, atomic force microscopy), and biomolecular (Raman spectroscopy) analyses. The effect of inhibiting eCyPA in the cardiac microenvironment was evaluated using a newly developed neutralizing anti-eCyPA monoclonal antibody. RESULTS We observed a significant accumulation of eCyPA in both human and murine-failing hearts. Importantly, higher eCyPA expression was associated with poor clinical outcomes in patients (P=0.043) and contractile dysfunction in mice (Pearson correlation coefficient, -0.73). Further, myocardial expression of eCyPA was critically associated with an increase in myocardial hypertrophy, inflammation, fibrosis, stiffness, and cardiac dysfunction in vivo. Antibody-based inhibition of eCyPA prevented (Ang II)-induced myocardial remodeling and dysfunction in mice. CONCLUSIONS Our study provides strong evidence of the pathogenic role of eCyPA in remodeling, myocardial stiffening, and dysfunction in heart failure. The findings suggest that antibody-based inhibition of eCyPA may offer a novel therapeutic strategy for nonischemic heart failure. Further research is needed to evaluate the translational potential of these interventions in human patients with cardiac hypertrophy.
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Affiliation(s)
- Manuel Sigle
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
| | - Anne-Katrin Rohlfing
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
| | - Melanie Cruz Santos
- Institute of Pharmacy, Pharmacology, Toxicology and Clinical Pharmacy (M.C.S., R.L.), University of Tübingen, Germany
| | - Timo Kopp
- Interfaculty Institute of Biochemistry (IFIB) (T.K., R.F., S.F.), University of Tübingen, Germany
| | - Konstantin Krutzke
- Institute for Applied Physics (K.K., V.G., T.E.S.), University of Tübingen, Germany
| | - Vincent Gidlund
- Interfaculty Institute of Biochemistry (IFIB) (T.K., R.F., S.F.), University of Tübingen, Germany
- Institute for Applied Physics (K.K., V.G., T.E.S.), University of Tübingen, Germany
| | - Ferdinand Kollotzek
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
- DFG Heisenberg Group Cardiovascular Thrombo-Inflammation and Translational Thrombocardiology (F.K., O.B.), University of Tübingen, Germany
| | - Julia Marzi
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine (J. Marzi, K.S.-L.), Eberhard Karls University Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," (J. Marzi, A.P., K.S.-L.), University of Tübingen, Germany
- NMI Natural and Medical Sciences Institute at the University of Tübingen Reutlingen, Germany (J. Marzi, K.S.-L.)
| | - Saskia von Ungern-Sternberg
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
- Now with Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Germany (S.U.-S.)
| | - Antti Poso
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," (J. Marzi, A.P., K.S.-L.), University of Tübingen, Germany
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland Kuopio (A.P.)
- Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität Tübingen, Germany (A.P.)
- Tübingen Center for Academic Drug Discovery and Development (TüCAD2), Tübingen, Germany (A.P.)
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Centre Heidelberg (DKFZ), Germany (M.H.)
- University Tübingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome (M.H.)
| | - Katja Schenke-Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine (J. Marzi, K.S.-L.), Eberhard Karls University Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," (J. Marzi, A.P., K.S.-L.), University of Tübingen, Germany
- NMI Natural and Medical Sciences Institute at the University of Tübingen Reutlingen, Germany (J. Marzi, K.S.-L.)
| | - Peter Seizer
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
- Now with Aalen, Germany (P.S.)
| | - Julia Möllmann
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (J. Möllmann, N.M.)
| | - Nikolaus Marx
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany (J. Möllmann, N.M.)
| | - Robert Feil
- Interfaculty Institute of Biochemistry (IFIB) (T.K., R.F., S.F.), University of Tübingen, Germany
| | - Susanne Feil
- Interfaculty Institute of Biochemistry (IFIB) (T.K., R.F., S.F.), University of Tübingen, Germany
| | - Robert Lukowski
- Institute of Pharmacy, Pharmacology, Toxicology and Clinical Pharmacy (M.C.S., R.L.), University of Tübingen, Germany
| | - Oliver Borst
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
- DFG Heisenberg Group Cardiovascular Thrombo-Inflammation and Translational Thrombocardiology (F.K., O.B.), University of Tübingen, Germany
| | - Tilman E Schäffer
- Institute for Applied Physics (K.K., V.G., T.E.S.), University of Tübingen, Germany
| | - Karin Anne Lydia Müller
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
| | - Meinrad P Gawaz
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
| | - David Heinzmann
- Department of Cardiology and Angiology (M.S., A.-K.R., F.K., S.U.-S., P.S., O.B., K.A.L.M., M.P.G., D.H.), Eberhard Karls University Tübingen, Germany
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Sun P, Li Y, Yu W, Chen J, Wan P, Wang Z, Zhang M, Wang C, Fu S, Mang G, Choi S, Du Z, Tang C, Li S, Shi G, Tian J, Dai J, Leng X. Low-intensity pulsed ultrasound improves myocardial ischaemia‒reperfusion injury via migrasome-mediated mitocytosis. Clin Transl Med 2024; 14:e1749. [PMID: 38951127 PMCID: PMC11216834 DOI: 10.1002/ctm2.1749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/09/2024] [Accepted: 06/13/2024] [Indexed: 07/03/2024] Open
Abstract
During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis-mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low-intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI-induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome-dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F-actin pathway. Meanwhile, F-actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS-induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome-dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non-invasive treatment for MIRI.
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Affiliation(s)
- Ping Sun
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
| | - Yifei Li
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
| | - Weidong Yu
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
| | - Jianfeng Chen
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
- Laboratory of Animal CenterThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Pingping Wan
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Zhuo Wang
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
| | - Maomao Zhang
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Chao Wang
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
| | - Shuai Fu
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
| | - Ge Mang
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Stephen Choi
- SXULTRASONIC Ltd. Kerry Rehabilitation Medicine Research InstituteShenzhenChina
| | - Zhuo Du
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Caiying Tang
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Song Li
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Guoxia Shi
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Jiawei Tian
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
| | - Jiannan Dai
- The Key Laboratory of Myocardial IschemiaHarbin Medical University, Ministry of EducationHarbinChina
- Department of CardiologyThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Xiaoping Leng
- Department of UltrasoundThe Second Affiliated Hospital of Harbin Medical UniversityHarbinChina
- Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang ProvinceHarbinChina
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Buckley LF, Libby P. Colchicine's Role in Cardiovascular Disease Management. Arterioscler Thromb Vasc Biol 2024; 44:1031-1041. [PMID: 38511324 PMCID: PMC11047118 DOI: 10.1161/atvbaha.124.319851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
Colchicine-an anti-inflammatory alkaloid-has assumed an important role in the management of cardiovascular inflammation ≈3500 years after its first medicinal use in ancient Egypt. Primarily used in high doses for the treatment of acute gout flares during the 20th century, research in the early 21st century demonstrated that low-dose colchicine effectively treats acute gout attacks, lowers the risk of recurrent pericarditis, and can add to secondary prevention of major adverse cardiovascular events. As the first Food and Drug Administration-approved targeted anti-inflammatory cardiovascular therapy, colchicine currently has a unique role in the management of atherosclerotic cardiovascular disease. The safe use of colchicine requires careful monitoring for drug-drug interactions, changes in kidney and liver function, and counseling regarding gastrointestinal upset. Future research should elucidate the mechanisms of anti-inflammatory effects of colchicine relevant to atherosclerosis, the potential role of colchicine in primary prevention, in other cardiometabolic conditions, colchicine's safety in cardiovascular patients, and opportunities for individualizing colchicine therapy using clinical and molecular diagnostics.
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Affiliation(s)
- Leo F. Buckley
- Department of Pharmacy, Brigham and Women’s Hospital, Boston MA
| | - Peter Libby
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston MA
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Dridi H, Santulli G, Bahlouli L, Miotto MC, Weninger G, Marks AR. Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart. Biomolecules 2023; 13:1409. [PMID: 37759809 PMCID: PMC10527470 DOI: 10.3390/biom13091409] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/13/2023] [Accepted: 09/17/2023] [Indexed: 09/29/2023] Open
Abstract
Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca2+) handling, mitochondrial Ca2+ overload, and oxidative stress. In cardiomyocytes, Ca2+ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca2+ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca2+ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca2+ handling in heart failure and the potential therapeutic strategies.
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Affiliation(s)
- Haikel Dridi
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY 10032, USA; (L.B.); (M.C.M.); (G.W.); (A.R.M.)
| | - Gaetano Santulli
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Laith Bahlouli
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY 10032, USA; (L.B.); (M.C.M.); (G.W.); (A.R.M.)
| | - Marco C. Miotto
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY 10032, USA; (L.B.); (M.C.M.); (G.W.); (A.R.M.)
| | - Gunnar Weninger
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY 10032, USA; (L.B.); (M.C.M.); (G.W.); (A.R.M.)
| | - Andrew R. Marks
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY 10032, USA; (L.B.); (M.C.M.); (G.W.); (A.R.M.)
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7
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Chen L, Zhou M, Li H, Liu D, Liao P, Zong Y, Zhang C, Zou W, Gao J. Mitochondrial heterogeneity in diseases. Signal Transduct Target Ther 2023; 8:311. [PMID: 37607925 PMCID: PMC10444818 DOI: 10.1038/s41392-023-01546-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 02/21/2023] [Accepted: 06/13/2023] [Indexed: 08/24/2023] Open
Abstract
As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.
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Affiliation(s)
- Long Chen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Mengnan Zhou
- Department of Pathogenic Biology, School of Basic Medical Science, China Medical University, Shenyang, 110001, China
| | - Hao Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Delin Liu
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Peng Liao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Shanghai Sixth People's Hospital Fujian, No. 16, Luoshan Section, Jinguang Road, Luoshan Street, Jinjiang City, Quanzhou, Fujian, China.
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Algoet M, Janssens S, Himmelreich U, Gsell W, Pusovnik M, Van den Eynde J, Oosterlinck W. Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends Cardiovasc Med 2023; 33:357-366. [PMID: 35181472 DOI: 10.1016/j.tcm.2022.02.005] [Citation(s) in RCA: 145] [Impact Index Per Article: 72.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/12/2022] [Accepted: 02/13/2022] [Indexed: 12/20/2022]
Abstract
Acute myocardial infarction is caused by a sudden coronary artery occlusion and leads to ischemia in the corresponding myocardial territory which generally results in myocardial necrosis. Without restoration of coronary perfusion, myocardial scar formation will cause adverse remodelling of the myocardium and heart failure. Successful introduction of percutaneous coronary intervention and surgical coronary artery bypass grafting made it possible to achieve early revascularisation/reperfusion, hence limiting the ischemic zone of myocardium. However, reperfusion by itself paradoxically triggers an exacerbated and accelerated injury in the myocardium, called ischemia-reperfusion (I/R) injury. This mechanism is partially driven by inflammation through multiple interacting pathways. In this review we summarize the current insights in mechanisms of I/R injury and the influence of altered inflammation. Multiple pharmacological and interventional therapeutic strategies (ischemic conditioning) have proven to be beneficial during I/R in preclinical models but were notoriously unsuccessful upon clinical translation. In this review we focus on common mechanisms of I/R injury, altered inflammation and potential therapeutic strategies. We hypothesize that a dual approach may be of value because I/R injury patients are predestined with multiple comorbidities and systemic low-grade inflammation, which requires targeted intervention before other strategies can be fully effective.
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Affiliation(s)
- Michiel Algoet
- Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
| | - Stefan Janssens
- Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
| | - Uwe Himmelreich
- Biomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Willy Gsell
- Biomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Matic Pusovnik
- Biomedical MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Jef Van den Eynde
- Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Helen B. Taussig Heart Center, The Johns Hopkins Hospital and School of Medicine, Baltimore, United States
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9
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Bughin F, Kovacsik H, Jaussent I, Solecki K, Aguilhon S, Vanoverschelde J, Zarqane H, Mercier J, Gouzi F, Roubille F, Dauvilliers Y. Impact of Obstructive Sleep Apnea Syndrome on Ventricular Remodeling after Acute Myocardial Infarction: A Proof-of-Concept Study. J Clin Med 2022; 11:jcm11216341. [PMID: 36362568 PMCID: PMC9656926 DOI: 10.3390/jcm11216341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/18/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Obstructive sleep apnea syndrome (OSA) is common in patients with acute myocardial infarction (AMI). Whether OSA impacts on the ventricular remodeling post-AMI remains unclear. We compared cardiac ventricular remodeling in patients assessed by cardiac magnetic resonance (CMR) imaging at baseline and six months after AMI based on the presence and severity of OSA. Methods: This prospective study included 47 patients with moderate to severe AMI. They all underwent CMR at inclusion and at six months after an AMI, and a polysomnography was performed three weeks after AMI. Left and right ventricular remodeling parameters were compared between patients based on the AHI, AHI in REM and NREM sleep, oxygen desaturation index, and daytime sleepiness. Results: Of the 47 patients, 49% had moderate or severe OSA with an AHI ≥ 15/h. No differences were observed between these patients and those with an AHI < 15/h for left ventricular end-diastolic and end-systolic volumes at six months. No association was found for left and right ventricular remodeling parameters at six months or for the difference between baseline and six months with polysomnographic parameters of OSA severity, nor with daytime sleepiness. Conclusions: Although with a limited sample size, our proof-of-concept study does not report an association between OSA and ventricular remodeling in patients with AMI. These results highlight the complexity of the relationships between OSA and post-AMI morbi-mortality.
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Affiliation(s)
- François Bughin
- PhyMedExp, University of Montpellier, INSERM, CNRS, CHU, 34090 Montpellier, France
- Pneumology Department, Clinique du Millénaire, 34000 Montpellier, France
| | - Hélène Kovacsik
- Department of Interventional and Cardiovascular Imaging, CHU, 34090 Montpellier, France
| | - Isabelle Jaussent
- Institute for Neurosciences of Montpellier INM, University of Montpellier, INSERM, 34000 Montpellier, France
| | - Kamila Solecki
- Cardiology Department, Clinique Beausoleil, 34070 Montpellier, France
| | - Sylvain Aguilhon
- Cardiology Department, INI-CRT, CHU de Montpellier, PhyMedExp, Université de Montpellier, INSERM, CNRS, 34090 Montpellier, France
| | | | - Hamid Zarqane
- Department of Interventional and Cardiovascular Imaging, CHU, 34090 Montpellier, France
| | - Jacques Mercier
- PhyMedExp, University of Montpellier, INSERM, CNRS, CHU, 34090 Montpellier, France
| | - Fares Gouzi
- PhyMedExp, University of Montpellier, INSERM, CNRS, CHU, 34090 Montpellier, France
| | - François Roubille
- Cardiology Department, INI-CRT, CHU de Montpellier, PhyMedExp, Université de Montpellier, INSERM, CNRS, 34090 Montpellier, France
| | - Yves Dauvilliers
- Unité du Sommeil, Centre National de Référence pour la Narcolepsie, CHU Montpellier, Hôpital Gui-de-Chauliac, Service de Neurologie, 34090 Montpellier, France
- Correspondence:
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10
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Naqvi N, Iismaa SE, Graham RM, Husain A. Mechanism-Based Cardiac Regeneration Strategies in Mammals. Front Cell Dev Biol 2021; 9:747842. [PMID: 34708043 PMCID: PMC8542766 DOI: 10.3389/fcell.2021.747842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/06/2021] [Indexed: 12/11/2022] Open
Abstract
Heart failure in adults is a leading cause of morbidity and mortality worldwide. It can arise from a variety of diseases, with most resulting in a loss of cardiomyocytes that cannot be replaced due to their inability to replicate, as well as to a lack of resident cardiomyocyte progenitor cells in the adult heart. Identifying and exploiting mechanisms underlying loss of developmental cardiomyocyte replicative capacity has proved to be useful in developing therapeutics to effect adult cardiac regeneration. Of course, effective regeneration of myocardium after injury requires not just expansion of cardiomyocytes, but also neovascularization to allow appropriate perfusion and resolution of injury-induced inflammation and interstitial fibrosis, but also reversal of adverse left ventricular remodeling. In addition to overcoming these challenges, a regenerative therapy needs to be safe and easily translatable. Failure to address these critical issues will delay the translation of regenerative approaches. This review critically analyzes current regenerative approaches while also providing a framework for future experimental studies aimed at enhancing success in regenerating the injured heart.
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Affiliation(s)
- Nawazish Naqvi
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
| | - Siiri E Iismaa
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Robert M Graham
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Ahsan Husain
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
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11
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Mewton N, Roubille F, Bresson D, Prieur C, Bouleti C, Bochaton T, Ivanes F, Dubreuil O, Biere L, Hayek A, Derimay F, Akodad M, Alos B, Haider L, El Jonhy N, Daw R, De Bourguignon C, Dhelens C, Finet G, Bonnefoy-Cudraz E, Bidaux G, Boutitie F, Maucort-Boulch D, Croisille P, Rioufol G, Prunier F, Angoulvant D. Effect of Colchicine on Myocardial Injury in Acute Myocardial Infarction. Circulation 2021; 144:859-869. [PMID: 34420373 PMCID: PMC8462445 DOI: 10.1161/circulationaha.121.056177] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Supplemental Digital Content is available in the text. Background: Inflammation is a key factor of myocardial damage in reperfused ST-segment–elevation myocardial infarction. We hypothesized that colchicine, a potent anti-inflammatory agent, may reduce infarct size (IS) and left ventricular (LV) remodeling at the acute phase of ST-segment–elevation myocardial infarction. Methods: In this double-blind multicenter trial, we randomly assigned patients admitted for a first episode of ST-segment–elevation myocardial infarction referred for primary percutaneous coronary intervention to receive oral colchicine (2-mg loading dose followed by 0.5 mg twice a day) or matching placebo from admission to day 5. The primary efficacy outcome was IS determined by cardiac magnetic resonance imaging at 5 days. The relative LV end-diastolic volume change at 3 months and IS at 3 months assessed by cardiac magnetic resonance imaging were among the secondary outcomes. Results: We enrolled 192 patients, 101 in the colchicine group and 91 in the control group. At 5 days, the gadolinium enhancement–defined IS did not differ between the colchicine and placebo groups with a mean of 26 interquartile range (IQR) [16–44] versus 28.4 IQR [14–40] g of LV mass, respectively (P=0.87). At 3 months follow-up, there was no significant difference in LV remodeling between the colchicine and placebo groups with a +2.4% (IQR, –8.3% to 11.1%) versus –1.1% (IQR, –8.0% to 9.9%) change in LV end-diastolic volume (P=0.49). Infarct size at 3 months was also not significantly different between the colchicine and placebo groups (17 IQR [10–28] versus 18 IQR [10–27] g of LV mass, respectively; P=0.92). The incidence of gastrointestinal adverse events during the treatment period was greater with colchicine than with placebo (34% versus 11%, respectively; P=0.0002). Conclusions: In this randomized, placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days did not reduce IS assessed by cardiac magnetic resonance imaging. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03156816.
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Affiliation(s)
- Nathan Mewton
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - François Roubille
- PhyMedExp, Université de Montpellier, INSERM, CNRS, Cardiology Department, CHU de Montpellier, France (F.R., M.A.)
| | - Didier Bresson
- Cardiology Division, University Hospital of Mulhouse, Hôpital Emile Muller, Mulhouse, France (D.B.)
| | - Cyril Prieur
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Claire Bouleti
- Université de Poitiers, CIC Inserm 1402n CHU de Poitiers, France (C.B., B.A.)
| | - Thomas Bochaton
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Fabrice Ivanes
- Cardiology Department CHRU de Tours and EA4245 T2i Tours University, France (F.I., D.A.)
| | - Olivier Dubreuil
- Centre Hospitalier Saint-Joseph Saint-Luc, Invasive Cardiology Department, Lyon, France (O.D.)
| | - Loïc Biere
- Institut MITOVASC, CNRS 6015 INSERM U1083, Université d'Angers, Cardiology Division, CHU Angers, France (L.B., F.P.)
| | - Ahmad Hayek
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - François Derimay
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Mariama Akodad
- PhyMedExp, Université de Montpellier, INSERM, CNRS, Cardiology Department, CHU de Montpellier, France (F.R., M.A.)
| | - Benjamin Alos
- Université de Poitiers, CIC Inserm 1402n CHU de Poitiers, France (C.B., B.A.)
| | - Lamis Haider
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Naoual El Jonhy
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Rachel Daw
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Charles De Bourguignon
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Carole Dhelens
- Pharmacy Department, FRIPHARM-RC (C.D.), Hospices Civils de Lyon, France
| | - Gérard Finet
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Eric Bonnefoy-Cudraz
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | | | - Florent Boutitie
- UMR 5558 CNRS UCBL Biostatistics Departement (F.B., D.M.-B.), Hospices Civils de Lyon, France.,INSERM CarMeN 1060, IRIS Team, Claude Bernard University, Lyon, France (F.B.)
| | - Delphine Maucort-Boulch
- UMR 5558 CNRS UCBL Biostatistics Departement (F.B., D.M.-B.), Hospices Civils de Lyon, France
| | - Pierre Croisille
- CREATIS CNRS 5220 INSERM U1206 Research Lab, Radiology Department, University Hospital/CHU Saint Etienne, France (P.C.)
| | - Gilles Rioufol
- Hôpital Cardiovasculaire Louis Pradel, Clinical Investigation Center, INSERM 1407 and INSERM CarMeN 1060, Hospices Civils de Lyon and Claude Bernard University, Lyon, France (N.M., C.P., T.B., A.H., F.D., L.H., N.E.J, R.D., C.D.B., G.F., E.B.-C., G.R.)
| | - Fabrice Prunier
- Institut MITOVASC, CNRS 6015 INSERM U1083, Université d'Angers, Cardiology Division, CHU Angers, France (L.B., F.P.)
| | - Denis Angoulvant
- Cardiology Department CHRU de Tours and EA4245 T2i Tours University, France (F.I., D.A.)
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12
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Tu H, Zhou YJ, Tang LJ, Xiong XM, Zhang XJ, Ali Sheikh MS, Zhang JJ, Luo XJ, Yuan C, Peng J. Combination of ponatinib with deferoxamine synergistically mitigates ischemic heart injury via simultaneous prevention of necroptosis and ferroptosis. Eur J Pharmacol 2021; 898:173999. [PMID: 33675785 DOI: 10.1016/j.ejphar.2021.173999] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/24/2021] [Accepted: 02/28/2021] [Indexed: 12/13/2022]
Abstract
Necroptosis, ferroptosis and cyclophilin D (Cyp D)-dependent necrosis contribute to myocardial ischemia/reperfusion (I/R) injury, and ponatinib, deferoxamine and cyclosporine are reported to inhibit necroptosis, ferroptosis and Cyp D-dependent necrosis, respectively. This study aims to explore whether the any two combination between ponatinib, deferoxamine and cyclosporine exerts a better cardioprotective effect on I/R injury than single medicine does. The H9c2 cells were subjected to 10 h of hypoxia (H) plus 4 h of reoxygenation (R) to establish H/R injury model. The effects of any two combination between ponatinib, deferoxamine and cyclosporine on H/R injury were examined. On this basis, a I/R injury model in rat hearts was established to focus on the effect of ponatinib, deferoxamine and their combination on myocardial I/R injury and the underlying mechanisms. In H/R-treated H9c2 cells, all three medicines can attenuate H/R injury (decrease in LDH release and necrosis percent). However, only the combination of ponatinib with deferoxamine exerted synergistic effect on reducing H/R injury, showing simultaneous suppression of necroptosis and ferroptosis. Expectedly, administration of ponatinib or deferoxamine either before or after ischemia could suppress necroptosis or ferroptosis in the I/R-treated rat hearts as they did in vitro, concomitant with a decrease in myocardial infarct size and creatine kinase release, and the combination therapy is more efficient than single medication. Based on these observations, we conclude that the combination of ponatinib with deferoxamine reduces myocardial I/R injury via simultaneous inhibition of necroptosis and ferroptosis.
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Affiliation(s)
- Hua Tu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Yuan-Jing Zhou
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Li-Jing Tang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Xiao-Ming Xiong
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Xiao-Jie Zhang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Md Sayed Ali Sheikh
- Internal Medicine Department, Cardiology, College of Medicine, Jouf University, Skaka, Aljouf, Saudi Arabia
| | - Jie-Jie Zhang
- Department of Obstetrics, Xiangya Hospital Central South University, Changsha, China; Hunan Engineering Research Center of Early Life Development and Disease Prevention, Changsha, China
| | - Xiu-Ju Luo
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Chuang Yuan
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
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Panel M, Ahmed-Belkacem A, Ruiz I, Guichou JF, Pawlotsky JM, Ghaleh B, Morin D. A Phenyl-Pyrrolidine Derivative Reveals a Dual Inhibition Mechanism of Myocardial Mitochondrial Permeability Transition Pore, Which Is Limited by Its Myocardial Distribution. J Pharmacol Exp Ther 2021; 376:348-357. [PMID: 33303698 DOI: 10.1124/jpet.120.000359] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/08/2020] [Indexed: 03/08/2025] Open
Abstract
Mitochondrial permeability transition pore (mPTP) opening is a key event in cell death during myocardial ischemia reperfusion. Inhibition of its modulator cyclophilin D (CypD) by cyclosporine A (CsA) reduces ischemia-reperfusion injury. The use of cyclosporine A in this indication is debated; however, targeting mPTP remains a major goal to achieve. We investigated the protective effects of a new original small-molecule cyclophilin inhibitor C31, which was specifically designed to target CypD. CypD peptidylprolyl cis-trans isomerase (PPIase) activity was assessed by the standard chemotrypsin-coupled assay. The effects of C31 on mPTP opening were investigated in isolated mouse cardiac mitochondria by measuring mitochondrial swelling and calcium retention capacity (CRC) in rat H9C2 cardiomyoblasts and in adult mouse cardiomyocytes by fluorescence microscopy in isolated perfused mouse hearts and ex vivo after drug infusion in mice. C31 potently inhibited CypD PPIase activity and mitochondrial swelling. C31 was more effective at increasing mitochondrial CRC than CsA and was still able to increase CRC in Ppif -/- (CypD-inactivated) cardiac mitochondria. C31 delayed both mPTP opening and cell death in cardiomyocytes subjected to hypoxia reoxygenation. However, high concentrations of both drugs were necessary to reduce mPTP opening in isolated perfused hearts, and neither CsA nor C31 inhibited mPTP opening in heart after in vivo infusion, underlying the importance of myocardial drug distribution for cardioprotection. C31 is an original inhibitor of mPTP opening involving both CypD-dependent and -independent mechanisms. It constitutes a promising new cytoprotective agent. Optimization of its pharmacokinetic properties is now required prior to its use against cardiac ischemia-reperfusion injury. SIGNIFICANCE STATEMENT: This study demonstrates that the new cyclophilin inhibitor C31 potently inhibits cardiac mitochondrial permeability transition pore (mPTP) opening in vitro and ex vivo. The dual mechanism of action of C31 allows the prevention of mPTP opening beyond cyclophilin D inhibition. Further development of the compound might bring promising drug candidates for cardioprotection. However, the lack of effect of both C31 and cyclosporine A after systemic administration demonstrates the difficulties of targeting myocardial mitochondria in vivo and should be taken into account in cardioprotective strategies.
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Affiliation(s)
- Mathieu Panel
- U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
| | - Abdelhakim Ahmed-Belkacem
- U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
| | - Isaac Ruiz
- U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
| | - Jean-François Guichou
- U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
| | - Jean-Michel Pawlotsky
- U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
| | - Bijan Ghaleh
- U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
| | - Didier Morin
- U955 - IMRB, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Créteil, France (M.P., B.G., D.M.);Université Paris-Est, UMR S955, UPEC, Créteil, France (A.A.B., I.R., J.M.P.); INSERM U955, Team « Viruses, Hepatology, Cancer », Hôpital Henri Mondor, Créteil, France (A.A.B., J.M.P., I.R.); Centre de Biochimie Structurale (CBS), INSERM U1054, CNRS UMR5048, Université de Montpellier, Montpellier, France (J.F.G.); and Department of Virology, Hôpital Henri Mondor, Créteil, France (J.M.P.)
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Abstract
Perioperative cardioprotection aims to minimize the consequences of myocardial ischemia-reperfusion injury. In isolated tissue and animal experiments, several treatments have been identified providing cardioprotection. Some of these strategies have been confirmed in clinical proof-of-concept studies. However, the final translation of cardioprotective strategies to really improve clinical outcome has been disappointing: large randomized controlled clinical trials mostly revealed inconclusive, neutral, or negative results. This review provides an overview of the currently available evidence regarding clinical implications of perioperative cardioprotective therapies from an anesthesiological perspective, highlighting nonpharmacological as well as pharmacological strategies. We discuss reasons why translation of promising experimental results into clinical practice and outcome improvement is hampered by potential confounders and suggest future perspectives to overcome these limitations.
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15
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de Miranda DC, de Oliveira Faria G, Hermidorff MM, Dos Santos Silva FC, de Assis LVM, Isoldi MC. Pre- and Post-Conditioning of the Heart: An Overview of Cardioprotective Signaling Pathways. Curr Vasc Pharmacol 2020; 19:499-524. [PMID: 33222675 DOI: 10.2174/1570161119666201120160619] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/02/2020] [Accepted: 11/02/2020] [Indexed: 11/22/2022]
Abstract
Since the discovery of ischemic pre- and post-conditioning, more than 30 years ago, the knowledge about the mechanisms and signaling pathways involved in these processes has significantly increased. In clinical practice, on the other hand, such advancement has yet to be seen. This article provides an overview of ischemic pre-, post-, remote, and pharmacological conditioning related to the heart. In addition, we reviewed the cardioprotective signaling pathways and therapeutic agents involved in the above-mentioned processes, aiming to provide a comprehensive evaluation of the advancements in the field. The advancements made over the last decades cannot be ignored and with the exponential growth in techniques and applications. The future of pre- and post-conditioning is promising.
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Affiliation(s)
- Denise Coutinho de Miranda
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Gabriela de Oliveira Faria
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Milla Marques Hermidorff
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Fernanda Cacilda Dos Santos Silva
- Laboratory of Cardiovascular Physiology, Department of Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Leonardo Vinícius Monteiro de Assis
- Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Mauro César Isoldi
- Laboratory of Cell Signaling, Research Center in Biological Science, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
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16
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The Melatonin Receptor Agonist Ramelteon Induces Cardioprotection that Requires MT2 Receptor Activation and Release of Reactive Oxygen Species. Cardiovasc Drugs Ther 2020; 34:303-310. [PMID: 32236860 PMCID: PMC7242242 DOI: 10.1007/s10557-020-06972-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Purpose The melatonin receptor (MT) agonist ramelteon has a higher affinity to MT1 than for MT2 receptors and induces cardioprotection by involvement of mitochondrial potassium channels. Activation of mitochondrial potassium channels leads to release of free radicals. We investigated whether (1) ramelteon-induced cardioprotection is MT2 receptor specific and (2) if free radicals are involved in ramelteon-induced cardioprotection. Methods Hearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia hearts were perfused with ramelteon (Ram) with or without the MT2 receptor inhibitor 4-phenyl-2-propionamidotetralin (4P-PDOT+Ram, 4P-PDOT). In subsequent experiments, ramelteon was administered together with the radical oxygen species (ROS) scavenger N-2-mercaptopropionylglycine (MPG+Ram). To determine whether the blockade of ramelteon-induced cardioprotection can be restored, we combined ramelteon and MPG with mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA) at different time points. Infarct size was determined by triphenyltetrazolium chloride (TTC) staining. Results Ramelteon-induced infarct size reduction was completely blocked by 4P-PDOT and MPG. Ramelteon and MPG combined with CsA before ischemia were not cardioprotective but CsA at the onset of reperfusion could restore infarct size reduction. Conclusions This study shows for the first time that despite the higher affinity to MT1 receptors, (1) ramelteon-induced cardioprotection involves MT2 receptors, (2) cardioprotection requires ROS release, and (3) inhibition of the mPTP can restore infarct size reduction.
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17
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Giblett JP, Bulluck H. Cardioprotection for Acute MI in Light of the CONDI2/ERIC-PPCI Trial: New Targets Needed. ACTA ACUST UNITED AC 2020; 15:e13. [PMID: 32944081 PMCID: PMC7479528 DOI: 10.15420/icr.2020.01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023]
Abstract
Protection against ischaemia-reperfusion injury after revascularisation in acute myocardial infarction remains an enigma. Many targets have been identified, but after the failure of the recent Effect of Remote Ischaemic Conditioning on Clinical Outcomes in ST-elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention (CONDI2/ERIC-PPCI) trial to show translation to clinical benefit, there is still no pharmacological or mechanical strategy that has translated to clinical practice. This article addresses the results of the CONDI2/ERIC-PPCI trial in the context of previous studies of ischaemic conditioning, and then considers the prospects for other potential targets of cardioprotection. Finally, the authors examine the pitfalls and challenges in trial design for future investigation of cardioprotective strategies. In particular, this article highlights the need for careful endpoint and patient selection, as well as the need to pay attention to the biology of cardioprotection during the study.
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Affiliation(s)
- Joel P Giblett
- Department of Cardiology, Liverpool Heart and Chest Hospital Liverpool, UK
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18
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Li J, Sun D, Li Y. Novel Findings and Therapeutic Targets on Cardioprotection of Ischemia/ Reperfusion Injury in STEMI. Curr Pharm Des 2020; 25:3726-3739. [PMID: 31692431 DOI: 10.2174/1381612825666191105103417] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/30/2019] [Indexed: 12/19/2022]
Abstract
Acute ST-segment elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality around the world. A large number of STEMI patients after the infarction gradually develop heart failure due to the infarcted myocardium. Timely reperfusion is essential to salvage ischemic myocardium from the infarction, but the restoration of coronary blood flow in the infarct-related artery itself induces myocardial injury and cardiomyocyte death, known as ischemia/reperfusion injury (IRI). The factors contributing to IRI in STEMI are complex, and microvascular obstruction, inflammation, release of reactive oxygen species, myocardial stunning, and activation of myocardial cell death are involved. Therefore, additional cardioprotection is required to prevent the heart from IRI. Although many mechanical conditioning procedures and pharmacological agents have been identified as effective cardioprotective approaches in animal studies, their translation into the clinical practice has been relatively disappointing due to a variety of reasons. With new emerging data on cardioprotection in STEMI over the past few years, it is mandatory to reevaluate the effectiveness of "old" cardioprotective interventions and highlight the novel therapeutic targets and new treatment strategies of cardioprotection.
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Affiliation(s)
- Jianqiang Li
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China
| | - Danghui Sun
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China
| | - Yue Li
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China
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19
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Bøtker HE, Cabrera-Fuentes HA, Ruiz-Meana M, Heusch G, Ovize M. Translational issues for mitoprotective agents as adjunct to reperfusion therapy in patients with ST-segment elevation myocardial infarction. J Cell Mol Med 2020; 24:2717-2729. [PMID: 31967733 PMCID: PMC7077531 DOI: 10.1111/jcmm.14953] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 12/16/2022] Open
Abstract
Pre‐clinical studies have indicated that mitoprotective drugs may add cardioprotection beyond rapid revascularization, antiplatelet therapy and risk modification. We review the clinical efficacy of mitoprotective drugs that have progressed to clinical testing comprising cyclosporine A, KAI‐9803, MTP131 and TRO 40303. Whereas cyclosporine may reduce infarct size in patients undergoing primary angioplasty as evaluated by release of myocardial ischaemic biomarkers and infarct size imaging, the other drugs were not capable of demonstrating this effect in the clinical setting. The absent effect leaves the role of the mitochondrial permeability transition pore for reperfusion injury in humans unanswered and indicates that targeting one single mechanism to provide mitoprotection may not be efficient. Moreover, the lack of effect may relate to favourable outcome with current optimal therapy, but conditions such as age, sex, diabetes, dyslipidaemia and concurrent medications may also alter mitochondrial function. However, as long as the molecular structure of the pore remains unknown and specific inhibitors of its opening are lacking, the mitochondrial permeability transition pore remains a target for alleviation of reperfusion injury. Nevertheless, taking conditions such as ageing, sex, comorbidities and co‐medication into account may be of paramount importance during the design of pre‐clinical and clinical studies testing mitoprotective drugs.
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Affiliation(s)
- Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
| | - Hector Alejandro Cabrera-Fuentes
- SingHealth Duke-NUS Cardiovascular Sciences Academic Clinical Programme and Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.,National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore.,Institute of Biochemistry, Medical School, Justus-Liebig University, Giessen, Germany.,Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Monterrey, Mexico.,Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russian Federation
| | - Marisol Ruiz-Meana
- Vall d'Hebron Institut de Recerca, University Hospital Vall d'Hebron-Universitat Autònoma, Barcelona, Spain.,Centro de Investigación Biomédica en Red-CV, CIBER-CV, Spain
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen. Medical School, Essen, Germany
| | - Michel Ovize
- CarMeN Laboratory, Hôpital Louis Pradel, Hospices Civils de Lyon, Université de Lyon and Explorations Fonctionnelles Cardiovasculaires, INSERM U1060, Lyon, France
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20
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Bozi LHM, Campos JC, Zambelli VO, Ferreira ND, Ferreira JCB. Mitochondrially-targeted treatment strategies. Mol Aspects Med 2019; 71:100836. [PMID: 31866004 DOI: 10.1016/j.mam.2019.100836] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/11/2019] [Accepted: 12/13/2019] [Indexed: 12/13/2022]
Abstract
Disruption of mitochondrial function is a common feature of inherited mitochondrial diseases (mitochondriopathies) and many other infectious and non-infectious diseases including viral, bacterial and protozoan infections, inflammatory and chronic pain, neurodegeneration, diabetes, obesity and cardiovascular diseases. Mitochondria therefore become an attractive target for developing new therapies. In this review we describe critical mechanisms involved in the maintenance of mitochondrial functionality and discuss strategies used to identify and validate mitochondrial targets in different diseases. We also highlight the most recent preclinical and clinical findings using molecules targeting mitochondrial bioenergetics, morphology, number, content and detoxification systems in common pathologies.
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Affiliation(s)
- Luiz H M Bozi
- Institute of Biomedical Sciences, University of Sao Paulo, Brazil
| | - Juliane C Campos
- Institute of Biomedical Sciences, University of Sao Paulo, Brazil
| | | | | | - Julio C B Ferreira
- Institute of Biomedical Sciences, University of Sao Paulo, Brazil; Department of Chemical and Systems Biology, School of Medicine, Stanford University, USA.
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21
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Díaz-Ruíz JL, Macías-López A, Alcalá-Vargas F, Guevara-Chávez JG, Mejía-Uribe A, Silva-Palacios A, Zúñiga-Muñoz A, Zazueta C, Buelna-Chontal M. Redox signaling in ischemic postconditioning protection involves PKCε and Erk1/2 pathways and converges indirectly in Nrf2 activation. Cell Signal 2019; 64:109417. [DOI: 10.1016/j.cellsig.2019.109417] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 01/29/2023]
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22
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Zhang J, Liu D, Zhang M, Zhang Y. Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond. Br J Pharmacol 2019; 176:4319-4339. [PMID: 29774530 PMCID: PMC6887687 DOI: 10.1111/bph.14363] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 04/20/2018] [Accepted: 04/30/2018] [Indexed: 12/30/2022] Open
Abstract
Excessive death of cardiac myocytes leads to many cardiac diseases, including myocardial infarction, arrhythmia, heart failure and sudden cardiac death. For the last several decades, most work on cell death has focused on apoptosis, which is generally considered as the only form of regulated cell death, whereas necrosis has been regarded to be an unregulated process. Recent findings reveal that necrosis also occurs in a regulated manner and that it is closely related to the physiology and pathophysiology of many organs, including the heart. The recognition of necrosis as a regulated process mandates a re-examination of cell death in the heart together with the mechanisms and therapy of cardiac diseases. In this study, we summarize the regulatory mechanisms of the programmed necrosis of cardiomyocytes, that is, the intrinsic (mitochondrial) and extrinsic (death receptor) pathways. Furthermore, the role of this programmed necrosis in various heart diseases is also delineated. Finally, we describe the currently known pharmacological inhibitors of several of the key regulatory molecules of regulated cell necrosis and the opportunities for their therapeutic use in cardiac disease. We intend to systemically summarize the recent progresses in the regulation and pathological significance of programmed cardiomyocyte necrosis along with its potential therapeutic applications to cardiac diseases. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.
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Affiliation(s)
- Junxia Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular MedicinePeking UniversityBeijingChina
| | - Dairu Liu
- State Key Laboratory of Membrane Biology, Institute of Molecular MedicinePeking UniversityBeijingChina
| | - Mao Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular MedicinePeking UniversityBeijingChina
| | - Yan Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular MedicinePeking UniversityBeijingChina
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23
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See Hoe LE, Bartnikowski N, Wells MA, Suen JY, Fraser JF. Hurdles to Cardioprotection in the Critically Ill. Int J Mol Sci 2019; 20:E3823. [PMID: 31387264 PMCID: PMC6695809 DOI: 10.3390/ijms20153823] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/26/2019] [Accepted: 08/03/2019] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the largest contributor to worldwide mortality, and the deleterious impact of heart failure (HF) is projected to grow exponentially in the future. As heart transplantation (HTx) is the only effective treatment for end-stage HF, development of mechanical circulatory support (MCS) technology has unveiled additional therapeutic options for refractory cardiac disease. Unfortunately, despite both MCS and HTx being quintessential treatments for significant cardiac impairment, associated morbidity and mortality remain high. MCS technology continues to evolve, but is associated with numerous disturbances to cardiac function (e.g., oxidative damage, arrhythmias). Following MCS intervention, HTx is frequently the destination option for survival of critically ill cardiac patients. While effective, donor hearts are scarce, thus limiting HTx to few qualifying patients, and HTx remains correlated with substantial post-HTx complications. While MCS and HTx are vital to survival of critically ill cardiac patients, cardioprotective strategies to improve outcomes from these treatments are highly desirable. Accordingly, this review summarizes the current status of MCS and HTx in the clinic, and the associated cardiac complications inherent to these treatments. Furthermore, we detail current research being undertaken to improve cardiac outcomes following MCS/HTx, and important considerations for reducing the significant morbidity and mortality associated with these necessary treatment strategies.
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Affiliation(s)
- Louise E See Hoe
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia.
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia.
| | - Nicole Bartnikowski
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Science and Engineering Faculty, Queensland University of Technology, Chermside 4032, Australia
| | - Matthew A Wells
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- School of Medical Science, Griffith University, Southport 4222, Australia
| | - Jacky Y Suen
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital, Chermside 4032, Australia
- Faculty of Medicine, University of Queensland, Chermside 4032, Australia
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24
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Serebryakova LI, Studneva IM, Ovchinnikov MV, Veselova OM, Molokoedov AS, Arzamastsev EV, Afanasyeva EY, Terekhova OA, Sidorova MV, Pisarenko OI. [Cardiometabolic efficacy and toxicological evaluation of a pharmacological galanin receptor agonist]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2019; 65:231-238. [PMID: 31258147 DOI: 10.18097/pbmc20196503231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The goal of this study was to examine effects of a novel galanin receptor agonist GalR1-3 [bAla14, His15]-galanine 2-15 (G), obtained by automatic solid-phase synthesis, on the metabolic state of the area at risk and the size of acute myocardial infarction (MI) in rats in vivo and evaluate its toxicity in BALB /c mice. In anesthetized rats, regional ischemia was simulated by coronary artery occlusion and then coronary blood flow was restored. The peptide G was administered intravenously (i.v.) with a bolus after a period of regional ischemia in the dose range of 0.25-3.0 mg/kg. The sizes of MI and the activities of creatine kinase-MB (СK-MB) and lactate dehydrogenase (LDH) in blood plasma were estimated. The effect of administration of the optimal dose of G (1.0 mg/kg) on myocardial content of adenine nucleotides (AN), phosphocreatine (PCr), creatine (Cr) and lactate was studied. I.v. administration of G to rats at a dose of 1.0 mg/kg slightly affected hemodynamic parameters, but reduced MI size by 40% and decreased plasma LDH and CK-MB activity by the end of reperfusion compared to control. These effects were accompanied by a significant improvement in energy state of area at risk (AAR) - an increase in myocardial content of ATP, åAN, PCr and åCr, and combined with a decrease in myocardial lactate level compared with the control. Toxicity of peptide G was studied with a single intraperitoneal injection of 0.5-3.0% solution of the peptide substance to mice. The absence of signs of intoxication and death of animals after G injection in the maximum possible dose did not allow determining the value of the average lethal dose. The results indicate therapeutic potential of the peptide G for preventing myocardial ischemia and reperfusion injury and feasibility for further study of its pharmacological properties and mechanisms of action.
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Affiliation(s)
| | - I M Studneva
- National Medical Research Center for Cardiology, Moscow, Russia
| | - M V Ovchinnikov
- National Medical Research Center for Cardiology, Moscow, Russia
| | - O M Veselova
- National Medical Research Center for Cardiology, Moscow, Russia
| | - A S Molokoedov
- National Medical Research Center for Cardiology, Moscow, Russia
| | - E V Arzamastsev
- National Medical Research Center for Cardiology, Moscow, Russia
| | - E Yu Afanasyeva
- National Medical Research Center for Cardiology, Moscow, Russia
| | - O A Terekhova
- National Medical Research Center for Cardiology, Moscow, Russia
| | - M V Sidorova
- National Medical Research Center for Cardiology, Moscow, Russia
| | - O I Pisarenko
- National Medical Research Center for Cardiology, Moscow, Russia
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25
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Bloemberg D, Quadrilatero J. Autophagy, apoptosis, and mitochondria: molecular integration and physiological relevance in skeletal muscle. Am J Physiol Cell Physiol 2019; 317:C111-C130. [PMID: 31017800 DOI: 10.1152/ajpcell.00261.2018] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Apoptosis and autophagy are processes resulting from the integration of cellular stress and death signals. Their individual importance is highlighted by the lethality of various mouse models missing apoptosis or autophagy-related genes. In addition to their independent roles, significant overlap exists with respect to the signals that stimulate these processes as well as their effector consequences. While these cellular systems exemplify the programming redundancies that underlie many fundamental biological mechanisms, their intertwined relationship means that dysfunction can promote pathology. Although both autophagic and apoptotic signaling are active in skeletal muscle during various diseases and atrophy, their specific roles here are somewhat unique. Given our growing understanding of how specific changes at the cellular level impact whole-organism physiology, there is an equally growing interest in pharmacological manipulation of apoptosis and/or autophagy for altering human physiology and health.
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Affiliation(s)
- Darin Bloemberg
- Department of Kinesiology, University of Waterloo , Waterloo, Ontario , Canada
| | - Joe Quadrilatero
- Department of Kinesiology, University of Waterloo , Waterloo, Ontario , Canada
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26
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Kiyuna LA, Albuquerque RPE, Chen CH, Mochly-Rosen D, Ferreira JCB. Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities. Free Radic Biol Med 2018; 129:155-168. [PMID: 30227272 PMCID: PMC6309415 DOI: 10.1016/j.freeradbiomed.2018.09.019] [Citation(s) in RCA: 134] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/28/2018] [Accepted: 09/14/2018] [Indexed: 02/06/2023]
Abstract
Mitochondrial dysfunction characterized by impaired bioenergetics, oxidative stress and aldehydic load is a hallmark of heart failure. Recently, different research groups have provided evidence that selective activation of mitochondrial detoxifying systems that counteract excessive accumulation of ROS, RNS and reactive aldehydes is sufficient to stop cardiac degeneration upon chronic stress, such as heart failure. Therefore, pharmacological and non-pharmacological approaches targeting mitochondria detoxification may play a critical role in the prevention or treatment of heart failure. In this review we discuss the most recent findings on the central role of mitochondrial dysfunction, oxidative stress and aldehydic load in heart failure, highlighting the most recent preclinical and clinical studies using mitochondria-targeted molecules and exercise training as effective tools against heart failure.
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Affiliation(s)
- Ligia Akemi Kiyuna
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Brazil
| | | | - Che-Hong Chen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, USA
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, USA
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27
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Bøtker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femminò S, García-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhäuser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schlüter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G. Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 2018; 113:39. [PMID: 30120595 PMCID: PMC6105267 DOI: 10.1007/s00395-018-0696-8] [Citation(s) in RCA: 327] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/18/2018] [Accepted: 08/03/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Palle-Juul Jensens Boulevard 99, 8200, Aarhus N, Denmark.
| | - Derek Hausenloy
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
- The National Institute of Health Research, University College London Hospitals Biomedial Research Centre, Research and Development, London, UK
- National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore
- Yon Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Salvatore Antonucci
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Kerstin Boengler
- Institute for Physiology, Justus-Liebig University Giessen, Giessen, Germany
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Soni Deshwal
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Yvan Devaux
- Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Fabio Di Lisa
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Moises Di Sante
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Panagiotis Efentakis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Saveria Femminò
- Department of Clinical and Biological Sciences, University of Torino, Turin, Italy
| | - David García-Dorado
- Experimental Cardiology, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain
| | - Zoltán Giricz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), IIS-Fundación Jiménez Díaz, CIBERCV, Madrid, Spain
| | - Efstathios Iliodromitis
- Second Department of Cardiology, Faculty of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nina Kaludercic
- Department of Biomedical Sciences, CNR Institute of Neuroscience, University of Padova, Via Ugo Bassi 58/B, 35121, Padua, Italy
| | - Petra Kleinbongard
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Markus Neuhäuser
- Department of Mathematics and Technology, Koblenz University of Applied Science, Remagen, Germany
- Institute for Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, Essen, Germany
| | - Michel Ovize
- Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Pradel, Lyon, France
- UMR, 1060 (CarMeN), Université Claude Bernard, Lyon1, Villeurbanne, France
| | - Pasquale Pagliaro
- Department of Clinical and Biological Sciences, University of Torino, Turin, Italy
| | - Michael Rahbek-Schmidt
- Department of Cardiology, Aarhus University Hospital, Palle-Juul Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Marisol Ruiz-Meana
- Experimental Cardiology, Vall d'Hebron Institut de Recerca (VHIR), Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain
| | | | - Rainer Schulz
- Institute for Physiology, Justus-Liebig University Giessen, Giessen, Germany
| | - Andreas Skyschally
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Catherine Wilder
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | - Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany.
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Abstract
Several interventions, such as ischemic preconditioning, remote pre/perconditioning, or postconditioning, are known to decrease lethal myocardial ischemia-reperfusion injury. While several signal transduction pathways become activated by such maneuvers, they all have a common end point, namely, the mitochondria. These organelles represent an essential target of the cardioprotective strategies, and the preservation of mitochondrial function is central for the reduction of ischemia-reperfusion injury. In the present review, we address the role of mitochondria in the different conditioning strategies; in particular, we focus on alterations of mitochondrial function in terms of energy production, formation of reactive oxygen species, opening of the mitochondrial permeability transition pore, and mitochondrial dynamics induced by ischemia-reperfusion.
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Affiliation(s)
- Kerstin Boengler
- Institute of Physiology, Justus-Liebig Universität , Giessen , Germany
| | - Günter Lochnit
- Institute of Biochemistry, Justus-Liebig Universität , Giessen , Germany
| | - Rainer Schulz
- Institute of Physiology, Justus-Liebig Universität , Giessen , Germany
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29
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Parviz Y, Waleed M, Vijayan S, Adlam D, Lavi S, Al Nooryani A, Iqbal J, Stone GW. Cellular and molecular approaches to enhance myocardial recovery after myocardial infarction. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2018; 20:351-364. [PMID: 29958820 DOI: 10.1016/j.carrev.2018.05.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 05/22/2018] [Accepted: 05/29/2018] [Indexed: 10/14/2022]
Abstract
Reperfusion therapy has resulted in significant improvement in post-myocardial infarction morbidity and mortality in over the last 4 decades. Nonetheless, it is well recognized that simply restoring patency of the epicardial artery may not stop or reverse damage at microvascular level, and myocardial salvage is often suboptimal. Numerous efforts have been undertaken to elucidate the mechanisms underlying extensive myonecrosis to facilitate the discovery of therapies to provide additional and incremental benefits over current therapeutic pathways. To date, conclusively effective strategies to promote myocardial recovery have not yet been established. Novel approaches are investigating the foundational cellular and molecular bases of myocardial ischemia and irreversible injury. Herein, we review the emerging concepts and proposed therapies that may improve myocardial protection and reduce infarct size. We examine the preclinical and clinical evidence for reduced infarct size with these strategies, including anti-inflammatory agents, intracellular ion channel modulators, agents affecting the reperfusion injury salvage kinase (RISK) and nitric oxide signaling pathways, modulators of mitochondrial function, anti-apoptotic agents, and stem cell and gene therapy. We review the potential reasons of failures to date and the potential for new strategies to further promote myocardial recovery and improve prognosis.
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Affiliation(s)
- Yasir Parviz
- New York Presbyterian Hospital, Columbia University Medical Centre and the Cardiovascular Research Foundation, New York, NY, USA.
| | | | | | - David Adlam
- Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, UK
| | - Shahar Lavi
- Division of Cardiology, London Health Sciences Centre, Western University, London, Ontario, Canada
| | | | - Javaid Iqbal
- South Yorkshire Cardiothoracic Centre, Northern General Hospital, Sheffield, UK
| | - Gregg W Stone
- New York Presbyterian Hospital, Columbia University Medical Centre and the Cardiovascular Research Foundation, New York, NY, USA
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30
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Rahman FA, Abdullah SS, Manan WZWA, Tan LTH, Neoh CF, Ming LC, Chan KG, Lee LH, Goh BH, Salmasi S, Wu DBC, Khan TM. Efficacy and Safety of Cyclosporine in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis. Front Pharmacol 2018; 9:238. [PMID: 29970999 PMCID: PMC6018391 DOI: 10.3389/fphar.2018.00238] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 03/02/2018] [Indexed: 11/18/2022] Open
Abstract
There are various studies that have addressed the use of Cyclosporine among patients with acute myocardial infarction (AMI). However, to date there is hardly any concise and systematically structured evidence that debate on the efficacy and safety of Cyclosporine in AMI patients. The aim of this review is to systematically summarize the overall evidence from published trials, and to conduct a meta-analysis in order to determine the efficacy and safety of Cyclosporine vs. placebo or control among patients with AMI. All randomized control trial (RCT) published in English language from January 2000 to August 2017 were included for the systematic review and meta-analysis. A total of six RCTs met the inclusion and were hence included in the systematic review and meta-analysis. Based on the performed meta-analysis, no significant difference was found between Cyclosporine and placebo in terms of left ventricular ejection fraction (LVEF) improvement (mean difference 1.88; 95% CI −0.99 to 4.74; P = 0.2), mortality rate (OR 1.01; 95% Cl 0.60 to 1.67, P = 0.98) and recurrent MI occurrence (OR 0.65; 95% Cl 0.29 to 1.45, P = 0.29), with no evidence of heterogeneity, when given to patients with AMI. Cyclosporine also did not significantly lessen the rate of rehospitalisation in AMI patients when compared to placebo (OR 0.91; 95% Cl 0.58 to 1.42, P = 0.68), with moderate heterogeneity (I2 = 46%). There was also no significant improvement in heart failure events between Cyclosporine and placebo in AMI patients (OR 0.63; 95% Cl 0.31 to 1.29, P = 0.21; I2 = 80%). No serious adverse events were reported in Cyclosporine group across all studies suggesting that Cyclosporine is well tolerated when given to patients with AMI. The use of Cyclosporine in this group of patients, however, did not result in better clinical outcomes vs. placebo at improving LVEF, mortality rate, recurrent MI, rehospitalisation and heart failure event.
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Affiliation(s)
- Firdaus A Rahman
- Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Malaysia
| | - Siti S Abdullah
- Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Malaysia
| | | | - Loh Teng-Hern Tan
- Novel Bacteria and Drug Discovery Research Group, School of Pharmacy, Monash University, Bandar Sunway, Malaysia
| | - Chin-Fen Neoh
- Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Malaysia
| | - Long Chiau Ming
- School of Pharmacy, KPJ Healthcare University College, Nilai, Malaysia
| | - Kok-Gan Chan
- International Genome Centre, Jiangsu University, Zhenjiang, China.,Division of Genetics and Molecular Biology, Faculty of Science, Institute of Biological Sciences, University of Malaya, Kuala Lumpur, Malaysia
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery Research Group, School of Pharmacy, Monash University, Bandar Sunway, Malaysia.,Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,School of Pharmacy, Monash University, Bandar Sunway, Malaysia.,Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University, Bandar Sunway, Malaysia.,Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes, Health and Well-being Cluster, Global Asia in the 21st Century Platform, Monash University, Bandar Sunway, Malaysia
| | - Bey-Hing Goh
- Novel Bacteria and Drug Discovery Research Group, School of Pharmacy, Monash University, Bandar Sunway, Malaysia.,Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,School of Pharmacy, Monash University, Bandar Sunway, Malaysia.,Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University, Bandar Sunway, Malaysia.,Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes, Health and Well-being Cluster, Global Asia in the 21st Century Platform, Monash University, Bandar Sunway, Malaysia
| | - Shahrzad Salmasi
- Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | | | - Tahir M Khan
- School of Pharmacy, Monash University, Bandar Sunway, Malaysia.,Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes, Health and Well-being Cluster, Global Asia in the 21st Century Platform, Monash University, Bandar Sunway, Malaysia.,Institute of Pharmaceutical Science, University of Veterinary and Animal Science, Lahore, Pakistan
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31
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Hidalgo A, Glass N, Ovchinnikov D, Yang SK, Zhang X, Mazzone S, Chen C, Wolvetang E, Cooper-White J. Modelling ischemia-reperfusion injury (IRI) in vitro using metabolically matured induced pluripotent stem cell-derived cardiomyocytes. APL Bioeng 2018; 2:026102. [PMID: 31069299 PMCID: PMC6481709 DOI: 10.1063/1.5000746] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 02/27/2018] [Indexed: 12/31/2022] Open
Abstract
Coronary intervention following ST-segment elevation myocardial infarction (STEMI) is the treatment of choice for reducing cardiomyocyte death but paradoxically leads to reperfusion injury. Pharmacological post-conditioning is an attractive approach to minimize Ischemia-Reperfusion Injury (IRI), but candidate drugs identified in IRI animal models have performed poorly in human clinical trials, highlighting the need for a human cell-based model of IRI. In this work, we show that when we imposed sequential hypoxia and reoxygenation episodes [mimicking the ischemia (I) and reperfusion (R) events] to immature human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), they display significant hypoxia resistance and minimal cell death (∼5%). Metabolic maturation of hPSC-CMs for 8 days substantially increased their sensitivity to changes in oxygen concentration and led to up to ∼30% cell death post-hypoxia and reoxygenation. To mimic the known transient changes in the interstitial tissue microenvironment during an IRI event in vivo, we tested a new in vitro IRI model protocol that required glucose availability and lowering of media pH during the ischemic episode, resulting in a significant increase in cell death in vitro (∼60%). Finally, we confirm that in this new physiologically matched IRI in vitro model, pharmacological post-conditioning reduces reperfusion-induced hPSC-CM cell death by 50%. Our results indicate that in recapitulating key aspects of an in vivo IRI event, our in vitro model can serve as a useful method for the study of IRI and the validation and screening of human specific pharmacological post-conditioning drug candidates.
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Affiliation(s)
| | - Nick Glass
- Tissue Engineering and Microfluidics Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, Australia
| | - Dmitry Ovchinnikov
- Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, Australia
| | - Seung-Kwon Yang
- Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, The University of Queensland, St. Lucia 4072, Australia
| | - Xinli Zhang
- Laboratory for Endocrinology and Metabolism, School of Biomedical Sciences, The University of Queensland, St. Lucia 4072, Australia
| | - Stuart Mazzone
- Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, The University of Queensland, St. Lucia 4072, Australia
| | - Chen Chen
- Laboratory for Endocrinology and Metabolism, School of Biomedical Sciences, The University of Queensland, St. Lucia 4072, Australia
| | - Ernst Wolvetang
- Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane 4072, Australia
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32
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Zhu P, Hu S, Jin Q, Li D, Tian F, Toan S, Li Y, Zhou H, Chen Y. Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: A mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biol 2018; 16:157-168. [PMID: 29502045 PMCID: PMC5952878 DOI: 10.1016/j.redox.2018.02.019] [Citation(s) in RCA: 299] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 02/18/2018] [Accepted: 02/19/2018] [Indexed: 12/16/2022] Open
Abstract
Receptor-interacting protein 3 (Ripk3)-mediated necroptosis contributes to cardiac ischaemia-reperfusion (IR) injury through poorly defined mechanisms. Our results demonstrated that Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H2O2. The higher level of Ripk3 was positively correlated to the infarction area expansion, cardiac dysfunction and augmented cardiomyocytes necroptosis. Function study further illustrated that upregulated Ripk3 evoked the endoplasmic reticulum (ER) stress, which was accompanied with an increase in intracellular Ca2+ level ([Ca2+]c) and xanthine oxidase (XO) expression. Activated XO raised cellular reactive oxygen species (ROS) that mediated the mitochondrial permeability transition pore (mPTP) opening and cardiomyocytes necroptosis. By comparison, genetic ablation of Ripk3 abrogated the ER stress and thus blocked the [Ca2+]c overload-XO-ROS-mPTP pathways, favouring a pro-survival state that ultimately resulted in the inhibition of cardiomyocytes necroptosis in the setting of cardiac IR injury. In summary, the present study helps to elucidate how necroptosis is mediated by ER stress, via the calcium overload /XO/ROS/mPTP opening axis.
ER stress is activated by Ripk3 in cardiac IR injury. ER stress induces calcium overload which triggers XO-dependent ROS overproduction. ROS outburst promotes mPTP opening that accounts for the necroptosis. Inhibiting ER stress favors cardiomyocytes survival and protects cardiac function.
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Affiliation(s)
- Pingjun Zhu
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Shunying Hu
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Qinhua Jin
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Dandan Li
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Feng Tian
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Sam Toan
- Department of Chemical and Environmental Engineering, University of California, Riverside, CA 92521 USA
| | - Yang Li
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Hao Zhou
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA.
| | - Yundai Chen
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
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33
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Hausenloy DJ, Garcia-Dorado D, Bøtker HE, Davidson SM, Downey J, Engel FB, Jennings R, Lecour S, Leor J, Madonna R, Ovize M, Perrino C, Prunier F, Schulz R, Sluijter JPG, Van Laake LW, Vinten-Johansen J, Yellon DM, Ytrehus K, Heusch G, Ferdinandy P. Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart. Cardiovasc Res 2018; 113:564-585. [PMID: 28453734 DOI: 10.1093/cvr/cvx049] [Citation(s) in RCA: 254] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic-however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial IRI.
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Affiliation(s)
- Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK; The National Institute of Health Research University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road London, W1T 7DN, UK; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore 169857; National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Dr, Singapore 169609, Singapore; Yong Loo Lin School of Medicine, National University Singapore, Singapore; Barts Heart Centre, St Bartholomew's Hospital, London, UK
| | - David Garcia-Dorado
- Department of Cardiology, Vall d Hebron University Hospital and Research Institute. Universitat Autònoma, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital Skejby, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK
| | - James Downey
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, 5851 USA Dr. N., MSB 3074, Mobile, AL 36688, USA
| | - Felix B Engel
- Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nßrnberg, Schloßplatz 4, 91054 Erlangen, Germany
| | - Robert Jennings
- Department of Cardiology, Duke University, Durham, NC 27708, USA
| | - Sandrine Lecour
- Department of Medicine, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Faculty of Health Sciences, University of Cape Town, Chris Barnard Building, Anzio Road, Observatory, 7925, Cape Town, Western Cape, South Africa
| | - Jonathan Leor
- Tamman Cardiovascular Research Institute, Sheba Medical Center, Tel Hashomer, Israel; Neufeld Cardiac Research Institute, Tel-Aviv University, Sheba Medical Center, Tel Hashomer, 5265601, Israel; Sheba Center for Regenerative Medicine, Stem Cell, and Tissue Engineering, Tel Hashomer, 5265601, Israel
| | - Rosalinda Madonna
- Center of Aging Sciences and Translational Medicine - CESI-MeT, "G. d'Annunzio" University, Chieti, Italy; Institute of Cardiology, Department of Neurosciences, Imaging, and Clinical Sciences, "G. d'Annunzio University, Chieti, Italy; Texas Heart Institute and University of Texas Medical School in Houston, Department of Internal Medicine, 6770 Bertner Avenue, Houston, Texas 77030 USA
| | - Michel Ovize
- Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Pradel, 28 Avenue du Doyen Jean Lépine, 69500 Bron, France; UMR 1060 (CarMeN), Université Claude Bernard Lyon, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France
| | - Cinzia Perrino
- Department of Advanced Biomedical Sciences, Division of Cardiology, Federico II University Corso Umberto I, 40, 80138 Napoli, Italy
| | - Fabrice Prunier
- Department of Cardiology, University of Angers, University Hospital of Angers, 4 Rue Larrey, 49100 Angers, France
| | - Rainer Schulz
- Institute of Physiology, Justus-Liebig, University of Giessen, Ludwigstraße 23, 35390 Gießen, Germany
| | - Joost P G Sluijter
- Cardiology and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands
| | - Linda W Van Laake
- Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands
| | - Jakob Vinten-Johansen
- Division of Cardiothoracic Surgery, Department of Surgery, Emory University, 201 Dowman Dr, Atlanta, GA 30322, USA
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK; The National Institute of Health Research University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road London, W1T 7DN, UK
| | - Kirsti Ytrehus
- Cardiovascular Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway
| | - Gerd Heusch
- Institute for Pathophysiology, West-German Heart and Vascular Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Nagyvárad tér 4, 1089 Hungary; Pharmahungary Group, Graphisoft Park, 7 Záhony street, Budapest, H-1031, Hungary
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34
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Kloner RA, Brown DA, Csete M, Dai W, Downey JM, Gottlieb RA, Hale SL, Shi J. New and revisited approaches to preserving the reperfused myocardium. Nat Rev Cardiol 2017; 14:679-693. [PMID: 28748958 PMCID: PMC5991096 DOI: 10.1038/nrcardio.2017.102] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Early coronary artery reperfusion improves outcomes for patients with ST-segment elevation myocardial infarction (STEMI), but morbidity and mortality after STEMI remain unacceptably high. The primary deficits seen in these patients include inadequate pump function, owing to rapid infarction of muscle in the first few hours of treatment, and adverse remodelling of the heart in the months that follow. Given that attempts to further reduce myocardial infarct size beyond early reperfusion in clinical trials have so far been disappointing, effective therapies are still needed to protect the reperfused myocardium. In this Review, we discuss several approaches to preserving the reperfused heart, such as therapies that target the mechanisms involved in mitochondrial bioenergetics, pyroptosis, and autophagy, as well as treatments that harness the cardioprotective properties of inhaled anaesthetic agents. We also discuss potential therapies focused on correcting the no-reflow phenomenon and its effect on healing and adverse left ventricular remodelling.
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Affiliation(s)
- Robert A Kloner
- Cardiovascular Research Institute, Huntington Medical Research Institutes, 99 North El Molino Avenue, Pasadena, California 91101, USA
- Division of Cardiovascular Medicine and Department of Medicine, Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, California 90033, USA
| | - David A Brown
- Department of Human Nutrition, Foods, and Exercise, 1981 Kraft Drive, Blacksburg, Virginia 24060, USA
- Virginia Tech Center for Drug Discovery, Virginia Tech, 1981 Kraft Drive, Blacksburg, Virginia 24060, USA
- Virginia Tech Metabolic Phenotyping Core, Virginia Tech, 1981 Kraft Drive, Blacksburg, Virginia 24060, USA
| | - Marie Csete
- Cardiovascular Research Institute, Huntington Medical Research Institutes, 99 North El Molino Avenue, Pasadena, California 91101, USA
- Department of Anesthesiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90017, USA
| | - Wangde Dai
- Cardiovascular Research Institute, Huntington Medical Research Institutes, 99 North El Molino Avenue, Pasadena, California 91101, USA
- Division of Cardiovascular Medicine and Department of Medicine, Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, California 90033, USA
| | - James M Downey
- Department of Physiology and Cell Biology, University of South Alabama, 5851 USA Drive North, Mobile, Alabama 36688, USA
| | - Roberta A Gottlieb
- Department of Medicine, Barbra Streisand Women's Heart Center, Heart Institute of Cedars-Sinai, Cedars-Sinai Medical Center, 127 South San Vicente Boulevard, Los Angeles, California 90048, USA
| | - Sharon L Hale
- Cardiovascular Research Institute, Huntington Medical Research Institutes, 99 North El Molino Avenue, Pasadena, California 91101, USA
| | - Jianru Shi
- Cardiovascular Research Institute, Huntington Medical Research Institutes, 99 North El Molino Avenue, Pasadena, California 91101, USA
- Division of Cardiovascular Medicine and Department of Medicine, Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, California 90033, USA
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35
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Stokfisz K, Ledakowicz-Polak A, Zagorski M, Zielinska M. Ischaemic preconditioning - Current knowledge and potential future applications after 30 years of experience. Adv Med Sci 2017; 62:307-316. [PMID: 28511069 DOI: 10.1016/j.advms.2016.11.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 10/19/2016] [Accepted: 11/29/2016] [Indexed: 12/16/2022]
Abstract
Ischaemic preconditioning (IPC) phenomenon has been known for thirty years. During that time several studies showed that IPC provided by brief ischaemic and reperfusion episodes prior to longer ischaemia can bestow a protective effect to both preconditioned and also remote organs. IPC affecting remote organs is called remote ischaemic preconditioning. Initially, most IPC studies were focused on enhancing myocardial resistance to subsequent ischaemia and reperfusion injury. However, preconditioning was found to be a universal phenomenon and was observed in various organs and tissues including the heart, liver, brain, retina, kidney, skeletal muscles and intestine. Currently, there are a lot of simultaneous studies are underway aiming at finding out whether IPC can be helpful in protecting these organs. The mechanism of local and remote IPC is complex and not well known. Several triggers, intracellular pathways and effectors, humoral, neural and induced by genetic changes may be considered potential pathways in the protective activity of local and remote IPC. Local and remote IPC mechanism may potentially serve as heart protection during cardiac surgery and may limit the infarct size of the myocardium, can be a strategy for preventing the development of acute kidney injury development and liver damage during transplantation, may protect the brain against ischaemic injury. In addition, the method is safe, non-invasive, cheap and easily applicable. The main purpose of this review article is to present new advances which would help to understand the potential mechanism of IPC. It also discusses both its potential applications and utility in clinical settings.
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Affiliation(s)
- Karolina Stokfisz
- Intensive Cardiac Therapy Clinic, Department of Invasive Cardiology and Electrocardiology, Medical University, Lodz, Poland.
| | - Anna Ledakowicz-Polak
- Intensive Cardiac Therapy Clinic, Department of Invasive Cardiology and Electrocardiology, Medical University, Lodz, Poland
| | - Maciej Zagorski
- Cardiosurgery Clinic, Department of Cardiology and Cardiosurgery, Medical University, Lodz, Poland
| | - Marzenna Zielinska
- Intensive Cardiac Therapy Clinic, Department of Invasive Cardiology and Electrocardiology, Medical University, Lodz, Poland
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36
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Muráriková M, Ferko M, Waczulíková I, Jašová M, Kancirová I, Murínová J, Ravingerová T. Changes in mitochondrial properties may contribute to enhanced resistance to ischemia-reperfusion injury in the diabetic rat heart. Can J Physiol Pharmacol 2017; 95:969-976. [PMID: 28683206 DOI: 10.1139/cjpp-2017-0211] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Diabetes mellitus, besides having deleterious effects, induces cardiac adaptation that may reduce the heart's susceptibility to ischemia-reperfusion (IR) injury. This study aimed to investigate whether changes in mitochondrial properties are involved in the mechanisms of increased resistance of the diabetic heart to IR. Adult male Wistar rats were made diabetic by a single dose of streptozotocin (65 mg·kg-1, i.p.), and on the day 8, Langendorff-perfused hearts were subjected to 30 min global ischemia and 40 min reperfusion. Baseline preischemic parameters in the diabetic hearts did not differ markedly from those in the nondiabetic controls, except for lower left ventricular developed pressure, higher mitochondrial membrane fluidity, and protein levels of manganese superoxide dismutase. On the other hand, diabetic hearts showed significantly better post-IR functional restoration and reduced arrhythmogenesis associated with lower reactive oxygen species production as compared with healthy controls. IR decreased membrane fluidity in both experimental groups; however, it led to a complete recovery of mitochondrial Mg2+-ATPase activity in diabetics in contrast to its reduction in nondiabetics. These findings indicate that the heart may become adapted to diabetes-induced alterations that might increase its tolerance to an ischemic insult. Preserved mitochondrial function might play a role in the mechanisms of the heart's resistance to IR injury in diabetics.
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Affiliation(s)
- Martina Muráriková
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Miroslav Ferko
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Iveta Waczulíková
- b Division of Biomedical Physics, Department of Nuclear Physics and Biophysics, Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovak Republic
| | - Magdaléna Jašová
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Ivana Kancirová
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Jana Murínová
- c Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Táňa Ravingerová
- a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic
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Pasupathy S, Tavella R, Grover S, Raman B, Procter NEK, Du YT, Mahadavan G, Stafford I, Heresztyn T, Holmes A, Zeitz C, Arstall M, Selvanayagam J, Horowitz JD, Beltrame JF. Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]). Circulation 2017. [PMID: 28634219 DOI: 10.1161/circulationaha.117.027575] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. METHODS This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging-assessed infarct size. Secondary end points included cardiac magnetic resonance-determined myocardial salvage and creatine kinase kinetics. RESULTS Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (P=0.08). CONCLUSIONS High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. CLINICAL TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.
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Affiliation(s)
- Sivabaskari Pasupathy
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Rosanna Tavella
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Suchi Grover
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Betty Raman
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Nathan E K Procter
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Yang Timothy Du
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Gnanadevan Mahadavan
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Irene Stafford
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Tamila Heresztyn
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Andrew Holmes
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Christopher Zeitz
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Margaret Arstall
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - Joseph Selvanayagam
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - John D Horowitz
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.)
| | - John F Beltrame
- From Discipline of Medicine, University of Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., Y.T.D., G.M., C.Z., M.A., J.D.H., J.F.B); Basil Hetzel Institute for Translational Health Research, Adelaide, Australia (S.P., R.T., B.R., N.E.K.P., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Central Adelaide Local Health Network, Australia (S.P., R.T., B.R., N.E.K.P., Y.D., G.M., I.S., T.H., A.H., C.Z., J.D.H., J.F.B); Northern Adelaide Local Health Network, Australia (G.M., C.Z., M.A., J.F.B.); Southern Adelaide Local Health Network, Australia (S.G., J.S.); Discipline of Medicine, Flinders University, Adelaide, Australia (S.G., J.S.); and South Australian Health and Medical Research Institute, Adelaide, Australia (J.S.).
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Pérez MJ, Quintanilla RA. Development or disease: duality of the mitochondrial permeability transition pore. Dev Biol 2017; 426:1-7. [PMID: 28457864 DOI: 10.1016/j.ydbio.2017.04.018] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/26/2017] [Accepted: 04/26/2017] [Indexed: 12/29/2022]
Abstract
Mitochondria is not only a dynamic organelle that produces ATP, but is also an important contributor to cell functions in both development and cell death processes. These paradoxical functions of mitochondria are partially regulated by the mitochondrial permeability transition pore (mPTP), a high-conductance channel that can induce loss of mitochondrial membrane potential, impairment of cellular calcium homeostasis, oxidative stress, and a decrease in ATP production upon pathological activation. Interestingly, despite their different etiologies, several neurodegenerative diseases and heart ischemic injuries share mitochondrial dysfunction as a common element. Generally, mitochondrial impairment is triggered by calcium deregulation that could lead to mPTP opening and cell death. Several studies have shown that opening of the mPTP not only induces mitochondrial damage and cell death, but is also a physiological mechanism involved in different cellular functions. The mPTP participates in regular calcium-release mechanisms that are required for proper metabolic regulation; it is hypothesized that the transient opening of this structure could be the principal mediator of cardiac and brain development. The mPTP also plays a role in protecting against different brain and cardiac disorders in the elderly population. Therefore, the aim of this work was to discuss different studies that show this controversial characteristic of the mPTP; although mPTP is normally associated with several pathological events, new critical findings suggest its importance in mitochondrial function and cell development.
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Affiliation(s)
- María José Pérez
- Laboratory of Neurodegenerative Diseases, Universidad Autónoma de Chile, Santiago, Chile
| | - Rodrigo A Quintanilla
- Laboratory of Neurodegenerative Diseases, Universidad Autónoma de Chile, Santiago, Chile; Centro de Investigación y Estudio del Consumo de Alcohol en Adolescentes (CIAA), Santiago, Chile.
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Boag SE, Andreano E, Spyridopoulos I. Lymphocyte Communication in Myocardial Ischemia/Reperfusion Injury. Antioxid Redox Signal 2017; 26:660-675. [PMID: 28006953 DOI: 10.1089/ars.2016.6940] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
SIGNIFICANCE Myocardial ischemia/reperfusion (I/R) is an important complication of reperfusion therapy for myocardial infarction (MI). It is a complex process involving metabolic and immunological factors. To date, no effective treatment has been identified. Recent Advances: Previous research has focused on the role of innate immune cells in I/R injury. In recent years, increasing evidence has accumulated for an important role for adaptive immune cells, particularly T lymphocytes. Data from ST elevation MI patients have identified prognostic significance for lymphocyte counts, particularly postreperfusion lymphopenia. Dynamic changes in circulating CD4+ T cell subsets occurring early after reperfusion are associated with development of I/R injury in the form of microvascular obstruction. Transcoronary gradients in cell counts suggest sequestration of these cells into the reperfused myocardium. These findings support existing data from mouse models indicating a role for CD4+ T cells in I/R injury. It is clear, however, the effects of lymphocytes in the ischemic myocardium are time and subset specific, with some having protective effects, while others are pathogenic. CRITICAL ISSUES An understanding of the cellular events that lead to accumulation of lymphocytes in the myocardium, and their actions once there, is key to manipulating this process. Chemokines produced in response to ischemia and cellular injury have an important role, while lymphocyte-derived cytokines are critical in the balance between inflammation and healing. FUTURE DIRECTIONS Further research into the involvement of lymphocytes in myocardial I/R injury may allow development of targeted therapies, opening a new avenue of considerable therapeutic potential. Antioxid. Redox Signal. 26, 660-675.
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Affiliation(s)
- Stephen E Boag
- 1 Institute of Genetic Medicine, Newcastle University , Newcastle upon Tyne, United Kingdom .,2 Regional Department of Clinical Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Emanuele Andreano
- 1 Institute of Genetic Medicine, Newcastle University , Newcastle upon Tyne, United Kingdom
| | - Ioakim Spyridopoulos
- 1 Institute of Genetic Medicine, Newcastle University , Newcastle upon Tyne, United Kingdom
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Liu CW, Yang F, Cheng SZ, Liu Y, Wan LH, Cong HL. Rosuvastatin postconditioning protects isolated hearts against ischemia-reperfusion injury: The role of radical oxygen species, PI3K-Akt-GSK-3β pathway, and mitochondrial permeability transition pore. Cardiovasc Ther 2017; 35:3-9. [PMID: 27580017 DOI: 10.1111/1755-5922.12225] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 05/04/2016] [Accepted: 08/26/2016] [Indexed: 11/28/2022] Open
Abstract
AIMS Glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore (mPTP) play an important role in myocardial ischemia-reperfusion injury. The aim of this study was to investigate whether postconditioning with rosuvastatin is able to reduce myocardial ischemia-reperfusion injury and clarify the potential mechanisms. METHODS Isolated rat hearts underwent 30 minutes of ischemia and 60 minutes of reperfusion in the presence or absence of rosuvastatin (1-50 nmol/L). The activity of signaling pathway was determined by Western blot analysis, and Ca2+ -induced mPTP opening was assessed by the use of a potentiometric method. RESULTS Rosuvastatin significantly reduced myocardial infarct size and improved cardiac function at 5 and 10 nmol/L. Protection disappeared at higher concentration and reverted to increased damage at 50 nmol/L. At 5 nmol/L, rosuvastatin increased the phosphorylation of protein kinase B (Akt) and GSK-3β, concomitant with a higher Ca2+ load required to open the mPTP. Rosuvastatin postconditioning also significantly increased superoxide dismutase activity and reduced malondialdehyde and radical oxygen species level. LY294002, phosphatidylinositol-3-kinase (PI3K) inhibitors, abolished these protective effects of rosuvastatin postconditioning. CONCLUSION Rosuvastatin prevents myocardial ischemia-reperfusion injury by inducing phosphorylation of PI3K-Akt and GSK-3β, preventing oxidative stress and subsequent inhibition of mPTP opening.
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Affiliation(s)
- Chun-Wei Liu
- Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China
| | - Fan Yang
- Department of Diagnostic Ultrasound, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Shi-Zhao Cheng
- Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin, China
| | - Yue Liu
- Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China
| | - Liang-Hui Wan
- Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China
| | - Hong-Liang Cong
- Department of Cardiology, Tianjin Medical University, Tianjin Chest Hospital, Tianjin, China
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Mitochondria in Structural and Functional Cardiac Remodeling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 982:277-306. [PMID: 28551793 DOI: 10.1007/978-3-319-55330-6_15] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The heart must function continuously as it is responsible for both supplying oxygen and nutrients throughout the entire body, as well as for the transport of waste products to excretory organs. When facing either a physiological or pathological increase in cardiac demand, the heart undergoes structural and functional remodeling as a means of adapting to increased workload. These adaptive responses can include changes in gene expression, protein composition, and structure of sub-cellular organelles involved in energy production and metabolism. Mitochondria are essential for cardiac function, as they supply the ATP necessary to support continuous cycles of contraction and relaxation. In addition, mitochondria carry out other important processes, including synthesis of essential cellular components, calcium buffering, and initiation of cell death signals. Not surprisingly, mitochondrial dysfunction has been linked to several cardiovascular disorders, including hypertension, cardiac hypertrophy, ischemia/reperfusion and heart failure. The present chapter will discuss how changes in mitochondrial cristae structure, fusion/fission dynamics, fatty acid oxidation, ATP production, and the generation of reactive oxygen species might impact cardiac structure and function, particularly in the context of pathological hypertrophy and fibrotic response. In addition, the mechanistic role of mitochondria in autophagy and programmed cell death of cardiomyocytes will be addressed. Here we will also review strategies to improve mitochondrial function and discuss their cardioprotective potential.
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Dominguez-Rodriguez A, Abreu-Gonzalez P, de la Torre-Hernandez JM, Gonzalez-Gonzalez J, Garcia-Camarero T, Consuegra-Sanchez L, Garcia-Saiz MDM, Aldea-Perona A, Virgos-Aller T, Azpeitia A, Reiter RJ. Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: Results of the Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty trial. J Pineal Res 2017; 62. [PMID: 27736028 DOI: 10.1111/jpi.12374] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 10/10/2016] [Indexed: 01/08/2023]
Abstract
The MARIA randomized trial evaluated the efficacy and safety of melatonin for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). This was a prespecified interim analysis. A total of 146 patients presenting with STEMI within 6 hours of chest pain onset were randomized to receive intravenous and intracoronary melatonin (n=73) or placebo (n=73) during primary percutaneous coronary intervention (PPCI). Primary endpoint was myocardial infarct size as assessed by magnetic resonance imaging (MRI) at 6 ± 2 days. Secondary endpoints were changes in left ventricular volumes and ejection fraction (LVEF) at 130 ± 10 days post-PPCI and adverse events during the first year. No significant differences in baseline characteristics were observed between groups. MRI was performed in 108 patients (86.4%). Myocardial infarct size by MRI evaluated 6 ± 2 days post-PPCI, did not differ between melatonin and placebo groups (P=.63). Infarct size assessed by MRI at 130 ± 10 days post-PPCI, performed in 91 patients (72.8%), did not show statistically significant differences between groups (P=.27). The recovery of LVEF from 6 ± 2 to 130 ± 10 days post-PPCI was greater in the placebo group (60.0 ± 10.4% vs 53.1 ± 12.5%, P=.008). Both left ventricular end-diastolic and end-systolic volumes were lower in the placebo group (P=.01). The incidence of adverse events at 1 year was comparable in both groups (P=.150). Thus, in a nonrestricted STEMI population, intravenous and intracoronary melatonin was not associated with a reduction in infarct size and has an unfavourable effect on the ventricular volumes and LVEF evolution. Likewise, there is lack of toxicity of melatonin with the doses used.
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Affiliation(s)
- Alberto Dominguez-Rodriguez
- Department of Cardiology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
- Facultad de Ciencias de la Salud, Universidad Europea de Canarias, La Orotava, Santa Cruz de Tenerife, Spain
| | - Pedro Abreu-Gonzalez
- Departamento de Ciencias Médicas Básicas (Unidad de Fisiología), Universidad de La Laguna, Santa Cruz de Tenerife, Spain
| | | | | | - Tamara Garcia-Camarero
- Department of Cardiology, Hospital Universitario Marques de Valdecilla, Santander, Cantabria, Spain
| | | | | | - Ana Aldea-Perona
- Department of Pharmacology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Tirso Virgos-Aller
- Department of Pharmacy, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | | | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
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Brown DA, Perry JB, Allen ME, Sabbah HN, Stauffer BL, Shaikh SR, Cleland JGF, Colucci WS, Butler J, Voors AA, Anker SD, Pitt B, Pieske B, Filippatos G, Greene SJ, Gheorghiade M. Expert consensus document: Mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol 2016; 14:238-250. [PMID: 28004807 PMCID: PMC5350035 DOI: 10.1038/nrcardio.2016.203] [Citation(s) in RCA: 538] [Impact Index Per Article: 59.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
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Affiliation(s)
- David A Brown
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, 1035 Integrated Life Sciences Building, 1981 Kraft Drive, Blacksburg, Virginia 24060, USA
| | - Justin B Perry
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, 1035 Integrated Life Sciences Building, 1981 Kraft Drive, Blacksburg, Virginia 24060, USA
| | - Mitchell E Allen
- Department of Human Nutrition, Foods, and Exercise, Virginia Tech, 1035 Integrated Life Sciences Building, 1981 Kraft Drive, Blacksburg, Virginia 24060, USA
| | - Hani N Sabbah
- Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202, USA
| | - Brian L Stauffer
- Division of Cardiology, Department of Medicine, University of Colorado Denver, 12700 East 19th Avenue, B139, Aurora, Colorado 80045, USA
| | - Saame Raza Shaikh
- Department of Biochemistry and Molecular Biology, East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, 115 Heart Drive, Greenville, North Carolina 27834, USA
| | - John G F Cleland
- National Heart &Lung Institute, National Institute of Health Research Cardiovascular Biomedical Research Unit, Royal Brompton &Harefield Hospitals, Imperial College, London, UK
| | - Wilson S Colucci
- Cardiovascular Medicine Section, Boston University School of Medicine and Boston Medical Center, 88 East Newton Street, C-8, Boston, Massachusetts 02118, USA
| | - Javed Butler
- Division of Cardiology, Health Sciences Center, T-16 Room 080, SUNY at Stony Brook, New York 11794, USA
| | - Adriaan A Voors
- University of Groningen, Department of Cardiology, University Medical Center Groningen, Groningen 9713 GZ, Netherlands
| | - Stefan D Anker
- Department of Innovative Clinical Trials, University Medical Centre Göttingen (UMG), Robert-Koch-Straße, D-37075, Göttingen, Germany
| | - Bertram Pitt
- University of Michigan School of Medicine, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA
| | - Burkert Pieske
- Department of Cardiology, Charité University Medicine, Campus Virchow Klinikum, and German Heart Center Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Gerasimos Filippatos
- National and Kopodistrian University of Athens, School of Medicine, Heart Failure Unit, Department of Cardiology, Athens University Hospital Attikon, Rimini 1, Athens 12462, Greece
| | - Stephen J Greene
- Division of Cardiology, Duke University Medical Center, 2301 Erwin Road Suite 7400, Durham, North Carolina 27705, USA
| | - Mihai Gheorghiade
- Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 201 East Huron, Galter 3-150, Chicago, Illinois 60611, USA
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44
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Mewton N, Elbaz M, Piot C, Ovize M. Infarct Size Reduction in Patients With STEMI: Why We Can Do It! J Cardiovasc Pharmacol Ther 2016; 16:298-303. [DOI: 10.1177/1074248411412379] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Major progress has been made over the last three decades for the treatment of patients with ST elevation myocardial infarction (STEMI). The major objective of this treatment is to reduce infarct size, which is the major prognostic factor in this population. Most of the efforts have been focused on improving reperfusion therapy in order to open as quickly as possible, and to prevent reocclusion, of the culprit coronary artery. During the past years, preclinical research has allowed researchers to well-characterize animal models of acute MI and precisely describe the major determinants of infarct size, that is area at risk, collateral flow, duration of ischemia, and timing of the protective intervention with respect to reflow. Recent reports have clearly demonstrated that lethal reperfusion injury exists, that it is of significant importance, and that it can be prevented by protective interventions applied immediately before reflow. Time has come to, on top of reperfusion therapy, better protect the muscle against lethal reperfusion injury. Although many past infarct size reduction studies have been negative, recent proof-of-concept studies have shown that infarct size reduction is possible in patients with STEMI, at least in part because the major determinants of infarct size have been taken into account. Accumulated knowledge from animal models together with encouraging results obtained in phase II infarct size reduction clinical trials should help us improve the design of future studies aimed at reducing infarct size in patients with STEMI.
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Affiliation(s)
- Nathan Mewton
- Inserm U 1060 (CARMEN), Lyon, France, Service d’Exploration Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, Université Claude Bernard Lyon1, Lyon, France
| | - Meier Elbaz
- Service de Cardiologie, Hôpital Rangueuil, University Paul Sabatier, Toulouse, France
| | - Christophe Piot
- Inserm U661, Montpellier, France, Hopital Arnaud de Villeneuve, Université de Montpellier I and II, Montpellier, France
| | - Michel Ovize
- Inserm U 1060 (CARMEN), Lyon, France, Service d’Exploration Fonctionnelles Cardiovasculaires, Hospices Civils de Lyon, Université Claude Bernard Lyon1, Lyon, France
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45
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Hausenloy DJ, Barrabes JA, Bøtker HE, Davidson SM, Di Lisa F, Downey J, Engstrom T, Ferdinandy P, Carbrera-Fuentes HA, Heusch G, Ibanez B, Iliodromitis EK, Inserte J, Jennings R, Kalia N, Kharbanda R, Lecour S, Marber M, Miura T, Ovize M, Perez-Pinzon MA, Piper HM, Przyklenk K, Schmidt MR, Redington A, Ruiz-Meana M, Vilahur G, Vinten-Johansen J, Yellon DM, Garcia-Dorado D. Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol 2016; 111:70. [PMID: 27766474 PMCID: PMC5073120 DOI: 10.1007/s00395-016-0588-8] [Citation(s) in RCA: 244] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 10/11/2016] [Indexed: 01/12/2023]
Abstract
To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research.
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Affiliation(s)
- Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, London, UK. .,The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK. .,Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore. .,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
| | - Jose A Barrabes
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital Skejby, 8200, Aarhus N, Denmark
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, UK
| | - Fabio Di Lisa
- Department of Biomedical Sciences and CNR Institute of Neurosciences, University of Padova, Padua, Italy
| | - James Downey
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Thomas Engstrom
- Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.,Pharmahungary Group, Szeged, Hungary
| | - Hector A Carbrera-Fuentes
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.,Institute for Biochemistry, Medical Faculty Justus-Liebig-University, Giessen, Germany.,Department of Microbiology, Kazan Federal University, Kazan, Russian Federation
| | - Gerd Heusch
- Institute for Pathophysiology, West-German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.,IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain
| | - Efstathios K Iliodromitis
- 2nd University Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Javier Inserte
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain
| | | | - Neena Kalia
- Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Rajesh Kharbanda
- Oxford Heart Centre, The John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK
| | - Sandrine Lecour
- Department of Medicine, Hatter Institute for Cardiovascular Research in Africa and South African Medical Research Council Inter-University Cape Heart Group, Faculty of Health Sciences, University of Cape Town, Chris Barnard Building, Anzio Road, Observatory, Cape Town, Western Cape, 7925, South Africa
| | - Michael Marber
- King's College London BHF Centre, The Rayne Institute, St. Thomas' Hospital, London, UK
| | - Tetsuji Miura
- Department of Cardiovascular, Renal, and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Michel Ovize
- Explorations Fonctionnelles Cardiovasculaires, Hôpital Louis Pradel, Lyon, France.,UMR 1060 (CarMeN), Université Claude Bernard, Lyon 1, France
| | - Miguel A Perez-Pinzon
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.,Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Hans Michael Piper
- Carl von Ossietzky Universität Oldenburg, Ökologiezentrum, Raum 2-116, Uhlhornsweg 99 b, 26129, Oldenburg, Germany
| | - Karin Przyklenk
- Department of Physiology and Emergency Medicine, Cardiovascular Research Institute, Wayne State University, Detroit, MI, USA
| | - Michael Rahbek Schmidt
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore, 169857, Singapore
| | - Andrew Redington
- Division of Cardiology, Department of Pediatrics, Heart Institute, Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Marisol Ruiz-Meana
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain
| | - Gemma Vilahur
- Cardiovascular Research Center, CSIC-ICCC, IIB-Hospital Sant Pau, c/Sant Antoni Maria Claret 167, 08025, Barcelona, Spain
| | - Jakob Vinten-Johansen
- Division of Cardiothoracic Surgery, Department of Surgery, Emory University, Atlanta, USA
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, UK.,The National Institute of Health Research University College London Hospitals Biomedical Research Centre, London, UK
| | - David Garcia-Dorado
- Department of Cardiology, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma, Barcelona, Spain.
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46
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Wang X, Hu YC, Zhang RY, Jin DX, Jiang Y, Zhang HN, Cong HL. Effect of cyclosporin A intervention on the immunological mechanisms of coronary heart disease and restenosis. Exp Ther Med 2016; 12:3242-3248. [PMID: 27882144 PMCID: PMC5103772 DOI: 10.3892/etm.2016.3775] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 07/15/2016] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the effect of cyclosporin A (CSA) intervention on the immunological mechanisms underlying coronary heart disease (CHD) and restenosis (RS) in rabbits. A total of 48 rabbits were randomly divided into normal control (N), N + CSA, CHD model, CHD + CSA, RS model and RS + CSA groups. Rabbits in the respective groups received different treatments prior to sacrifice at the end of week 12. Iliac arteries were harvested from the rabbits for morphological analysis and to determine the mRNA and protein expression levels of cluster of differentiation (CD) 40/CD40 ligand (CD40L), CD134/CD134 ligand (CD134L) and inflammatory factors, including matrix metalloproteinase (MMP)-1, MMP-9, vascular cell adhesion protein (VCAM)-1, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, by reverse transcription-quantitative polymerase chain reaction and immunohistochemical staining. As compared with the N group, the mRNA expression levels of MMP-9, VCAM-1 and TNF-α were significantly increased in the CHD and RS groups (P<0.05), but were significantly decreased in the groups with CSA intervention, as compared with those without CSA intervention (P<0.05). Conversely, there were no significant differences in the expression levels of MMP-1 and IL-6 among the six groups, although a decreasing trend of IL-6 expression was observed following intervention with CSA. Furthermore, there were significant differences in the mRNA and protein expression levels of CD40/CD40L and CD134/CD134L among the N, CHD and RS groups (P<0.05), and between the groups with and without CSA intervention. The present study demonstrated that CSA intervention exerted beneficial effects on CHD and RS, and further studies are required to investigate the mechanisms underlying the effects of CSA on CHD.
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Affiliation(s)
- Xuan Wang
- Cardiology Department, Tianjin Medical University, Tianjin 300070, P.R. China; Cardiology Department, Tianjin Chest Hospital, Tianjin 300222, P.R. China
| | - Yue-Cheng Hu
- Cardiology Department, Tianjin Chest Hospital, Tianjin 300222, P.R. China
| | - Ru-Yan Zhang
- Cardiology Department, Tianjin Chest Hospital, Tianjin 300222, P.R. China
| | - Dong-Xia Jin
- Cardiology Department, Tianjin Chest Hospital, Tianjin 300222, P.R. China
| | - Yuan Jiang
- Cardiology Department, Tianjin Medical University, Tianjin 300070, P.R. China
| | - He-Nan Zhang
- Cardiology Department, Tianjin Chest Hospital, Tianjin 300222, P.R. China
| | - Hong-Liang Cong
- Cardiology Department, Tianjin Chest Hospital, Tianjin 300222, P.R. China
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47
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Yingzhong C, Lin C, Chunbin W. Clinical effects of cyclosporine A on reperfusion injury in myocardial infarction: a meta-analysis of randomized controlled trials. SPRINGERPLUS 2016; 5:1117. [PMID: 27478734 PMCID: PMC4949180 DOI: 10.1186/s40064-016-2751-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 07/04/2016] [Indexed: 11/10/2022]
Abstract
Reperfusion therapy is the most crucial strategy for rescuing ischemic myocardium and reducing infarction size. Cyclosporine A (CsA) can protect against reperfusion-induced myocardial necrosis. However, the clinical effects of CsA on myocardial infarction (MI) remain uncertain. This study investigated the effects of CsA on reperfusion injury (RI) in MI. We searched for and included articles regarding randomized controlled trials investigating the effect of CsA in patients with MI from PubMed, EMBASE, and Cochrane Library databases for an analysis. We then performed quality assessment, subgroup, sensitivity, and publication bias analyses. Of the 277 potentially relevant articles retrieved from the databases, only five were eligible for our meta-analysis. Compared with the placebos used in these studies, CsA did not reduce all-cause mortality [rate ratio (RR) 1.10, 95 % confidence interval (CI) 0.75-1.61; P = 0.533; I (2) = 0 %) or adverse clinical events (RR 1.0, 95 % CI 0.89-1.13; P = 0.381; I (2) = 6.5 %). In the CsA treatment groups, improvement in left ventricular ejection fraction (weighted mean difference = 1.91; 95 % CI 0.89, 2.92; P = 0.064) and reduction in MI size (standard mean difference = -0.41, 95 % CI -0.84 to 0.02; P = 0.519; I (2) = 0.0 %) were minimal. The current meta-analysis indicates that CsA treatment does not reduce all-cause mortality and adverse clinical events in MI and that CsA may not have significant clinical effects on RI in MI.
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Affiliation(s)
- Chen Yingzhong
- Cardiovascular Disease Research Institute, The Third People's Hospital of Chengdu, The Second Affiliated Chengdu Clinical College of Chongqing Medical University, Sichuan, China
| | - Cai Lin
- Cardiovascular Disease Research Institute, The Third People's Hospital of Chengdu, The Second Affiliated Chengdu Clinical College of Chongqing Medical University, Sichuan, China
| | - Wang Chunbin
- Cardiovascular Disease Research Institute, The Third People's Hospital of Chengdu, The Second Affiliated Chengdu Clinical College of Chongqing Medical University, Sichuan, China ; Department of Cardiology, The Third People's Hospital of Chengdu, Chengdu, 610031 Sichuan China
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48
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Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GW, Kitsis RN, Otsu K, Ping P, Rizzuto R, Sack MN, Wallace D, Youle RJ. Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association. Circ Res 2016; 118:1960-91. [PMID: 27126807 PMCID: PMC6398603 DOI: 10.1161/res.0000000000000104] [Citation(s) in RCA: 321] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.
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49
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Bonaventura A, Montecucco F, Dallegri F. Cellular recruitment in myocardial ischaemia/reperfusion injury. Eur J Clin Invest 2016; 46:590-601. [PMID: 27090739 DOI: 10.1111/eci.12633] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 04/17/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Myocardial infarction (MI) is strictly linked to atherosclerosis. Beyond the mechanical narrowing of coronary vessels lumen, during MI a great burden of inflammation is carried out. One of the crucial events is represented by the ischaemia/reperfusion injury, a complex event involving inflammatory cells (such as neutrophils, platelets, monocytes/macrophages, lymphocytes and mast cells) and key activating signals (such as cytokines, chemokines and growth factors). Cardiac repair following myocardial infarction is dependent on a finely regulated response involving a sequential recruitment and the clearance of different subsets of inflammatory cells. MATERIALS AND METHODS This narrative review was based on the works detected on PubMed and MEDLINE up to November 2015. RESULTS Infarct healing classically follows three overlapping phases: the inflammatory phase, in which the innate immune pathways are activated and inflammatory leucocytes are recruited in order to clear the wound from dead cells; the proliferative phase, characterized by the suppression of pro-inflammatory signalling and infiltration of 'repairing' cells secreting matrix proteins in the injured area; and the maturation phase, which is associated with the quiescence and the elimination of the reparative cells together with cross-linking of the matrix. All these phases are timely regulated by the production of soluble mediators, such as cytokines, chemokines and growth factors. CONCLUSION Targeting inflammatory cell recruitment early during reperfusion and healing might be promising to selectively inhibit injury and favour repair. This approach might substantially improve adverse postischaemic left ventricle remodelling, characterized by dilation, hypertrophy of viable segments and progressive dysfunction.
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Affiliation(s)
- Aldo Bonaventura
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.,IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.,IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - Franco Dallegri
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.,IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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50
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Ottani F, Latini R, Staszewsky L, La Vecchia L, Locuratolo N, Sicuro M, Masson S, Barlera S, Milani V, Lombardi M, Costalunga A, Mollichelli N, Santarelli A, De Cesare N, Sganzerla P, Boi A, Maggioni AP, Limbruno U. Cyclosporine A in Reperfused Myocardial Infarction: The Multicenter, Controlled, Open-Label CYCLE Trial. J Am Coll Cardiol 2016; 67:365-374. [PMID: 26821623 DOI: 10.1016/j.jacc.2015.10.081] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 10/23/2015] [Accepted: 10/27/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Whether cyclosporine A (CsA) has beneficial effects in reperfused myocardial infarction (MI) is debated. OBJECTIVES This study investigated whether CsA improved ST-segment resolution in a randomized, multicenter phase II study. METHODS The authors randomly assigned 410 patients from 31 cardiac care units, age 63 ± 12 years, with large ST-segment elevation MI within 6 h of symptom onset, Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1 in the infarct-related artery, and committed to primary percutaneous coronary intervention, to 2.5 mg/kg intravenous CsA (n = 207) or control (n = 203) groups. The primary endpoint was incidence of ≥70% ST-segment resolution 60 min after TIMI flow grade 3. Secondary endpoints included high-sensitivity cardiac troponin T (hs-cTnT) on day 4, left ventricular (LV) remodeling, and clinical events at 6-month follow-up. RESULTS Time from symptom onset to first antegrade flow was 180 ± 67 min; a median of 5 electrocardiography leads showed ST-segment deviation (quartile [Q]1 to Q3: 4 to 6); 49.8% of MIs were anterior. ST-segment resolution ≥70% was found in 52.0% of CsA patients and 49.0% of controls (p = 0.55). Median hs-cTnT on day 4 was 2,160 (Q1 to Q3: 1,087 to 3,274) ng/l in CsA and 2,068 (1,117 to 3,690) ng/l in controls (p = 0.85). The 2 groups did not differ in LV ejection fraction on day 4 and at 6 months. Infarct site did not influence CsA efficacy. There were no acute allergic reactions or nonsignificant excesses of 6-month mortality (5.7% CsA vs. 3.2% controls, p = 0.17) or cardiogenic shock (2.4% CsA vs. 1.5% controls, p = 0.33). CONCLUSIONS In the CYCLE (CYCLosporinE A in Reperfused Acute Myocardial Infarction) trial, a single intravenous CsA bolus just before primary percutaneous coronary intervention had no effect on ST-segment resolution or hs-cTnT, and did not improve clinical outcomes or LV remodeling up to 6 months. (CYCLosporinE A in Reperfused Acute Myocardial Infarction [CYCLE]; NCT01650662; EudraCT number 2011-002876-18).
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Affiliation(s)
- Filippo Ottani
- Unità Operativa di Cardiologia, Ospedale GB Morgagni, Forlì, Italy
| | - Roberto Latini
- Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
| | - Lidia Staszewsky
- Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | | | | | - Marco Sicuro
- Cardiologia e UTIC, Ospedale Regionale Umberto Parini, Aosta, Italy
| | - Serge Masson
- Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Simona Barlera
- Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Valentina Milani
- Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Mario Lombardi
- Unità Operativa di Cardiologia, Ospedali Riuniti Villa Sofia, Palermo, Italy
| | | | | | | | | | - Paolo Sganzerla
- Cardiologia, Ospedale Treviglio-Caravaggio, Treviglio, Italy
| | - Alberto Boi
- Struttura Complessa di Emodinamica, Azienda Ospedaliera Brotzu, Cagliari, Italy
| | | | - Ugo Limbruno
- Cardiologia, Ospedale delle Misericordie, Grosseto, Italy
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