|
1
|
Wang K, Zhu Q, Liu W, Wang L, Li X, Zhao C, Wu N, Ma C. Mitochondrial apoptosis in response to cardiac ischemia-reperfusion injury. J Transl Med 2025; 23:125. [PMID: 39875870 PMCID: PMC11773821 DOI: 10.1186/s12967-025-06136-8] [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: 10/10/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
In patients with acute myocardial infarction (AMI), thrombolytic therapy and revascularization strategies allow complete recanalization of occluded epicardial coronary arteries. However, approximately 35% of patients still experience myocardial ischemia/reperfusion (I/R) injury, which contributing to increased AMI mortality. Therefore, an accurate understanding of myocardial I/R injury is important for preventing and treating AMI. The death of each cell (cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells) after myocardial ischemia/reperfusion is associated with apoptosis due to mitochondrial dysfunction. Abnormal opening of the mitochondrial permeability transition pore, aberrant mitochondrial membrane potential, Ca2+ overload, mitochondrial fission, and mitophagy can lead to mitochondrial dysfunction, thereby inducing mitochondrial apoptosis. The manifestation of mitochondrial apoptosis varies according to cell type. Here, we reviewed the characteristics of mitochondrial apoptosis in cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells following myocardial ischemia/reperfusion.
Collapse
Affiliation(s)
- Kaixin Wang
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Qing Zhu
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Wen Liu
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Linyuan Wang
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Xinxin Li
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Cuiting Zhao
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China
| | - Nan Wu
- The Central Laboratory of The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chunyan Ma
- Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China.
- Clinical Medical Research Center of Imaging in Liaoning Province, Shenyang, China.
| |
Collapse
|
|
2
|
Sonin DL, Medved MS, Khapchaev AY, Sidorova MV, Palkeeva ME, Kazakova OA, Papayan GV, Mochalov DA, Minasyan SM, Anufriev IE, Mukhametdinova DV, Paramonova NM, Balabanova KM, Lopatina AS, Aleksandrov IV, Semenova NY, Kordyukova AA, Zaichenko KV, Shirinsky VP, Galagudza MM. Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury. Curr Issues Mol Biol 2025; 47:33. [PMID: 39852148 PMCID: PMC11763459 DOI: 10.3390/cimb47010033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 12/28/2024] [Accepted: 01/03/2025] [Indexed: 01/26/2025] Open
Abstract
Myocardial ischemia-reperfusion injury increases myocardial microvascular permeability, leading to enhanced microvascular filtration and interstitial fluid accumulation that is associated with greater microvascular obstruction and inadequate myocardial perfusion. A burst of reactive oxygen species and inflammatory mediators during reperfusion causes myosin light chain kinase (MLCK)-dependent endothelial hyperpermeability, which is considered a preventable cause of reperfusion injury. In the present study, a single intravenous injection of MLCK peptide inhibitor PIK7 (2.5 mg/kg or 40 mg/kg) was found to suppress the vascular hyperpermeability caused by ischemia/reperfusion injury in an in vivo rat model. The antiedemic effect of PIK7 is transient and ceases within 90 min of reperfusion. The early no-reflow detected for the first time after 30 min ischemia in this model of myocardial infarction reduces the area accessible for PIK7. Electron microscopy has shown membrane-bound blebs of endotheliocytes, which partially or completely obturate the capillary lumen, and few capillaries with signs of intercellular gap formation in samples obtained from the center of the early no-reflow zone in control and PIK7-injected rats. Co-injection of PIK7 with NO donor sodium nitroprusside (SNP) increases blood flow in the zone of early no-reflow, while reducing the increased vascular permeability caused by SNP.
Collapse
Affiliation(s)
- Dmitry L. Sonin
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
- Laboratory of Radio- and Optoelectronic Devices for Early Diagnostics of Living Systems Pathologies, The Institute for Analytical Instrumentation, Russian Academy of Sciences, 31-33A Ivana Chernykh Street, 198095 Saint Petersburg, Russia; (A.A.K.); (K.V.Z.)
| | - Mikhail S. Medved
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Asker Y. Khapchaev
- Institute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia; (A.Y.K.); (M.V.S.); (M.E.P.); (O.A.K.); (V.P.S.)
| | - Maria V. Sidorova
- Institute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia; (A.Y.K.); (M.V.S.); (M.E.P.); (O.A.K.); (V.P.S.)
| | - Marina E. Palkeeva
- Institute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia; (A.Y.K.); (M.V.S.); (M.E.P.); (O.A.K.); (V.P.S.)
| | - Olga A. Kazakova
- Institute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia; (A.Y.K.); (M.V.S.); (M.E.P.); (O.A.K.); (V.P.S.)
| | - Garry V. Papayan
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
- Scientific and Educational Institute of Biomedicine, Pavlov First Saint Petersburg State Medical University, 6–8 Lev Tolstoy Street, 197022 Saint Petersburg, Russia
| | - Daniil A. Mochalov
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Sarkis M. Minasyan
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
- Scientific and Educational Institute of Biomedicine, Pavlov First Saint Petersburg State Medical University, 6–8 Lev Tolstoy Street, 197022 Saint Petersburg, Russia
| | - Ilya E. Anufriev
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
- Infochemistry Scientific Center, ITMO University, Lomonosova Str. 9, 191002 Saint-Petersburg, Russia
| | - Daria V. Mukhametdinova
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Natalia M. Paramonova
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Ksenia M. Balabanova
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Anastasia S. Lopatina
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Ilia V. Aleksandrov
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Natalya Yu. Semenova
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
| | - Anna A. Kordyukova
- Laboratory of Radio- and Optoelectronic Devices for Early Diagnostics of Living Systems Pathologies, The Institute for Analytical Instrumentation, Russian Academy of Sciences, 31-33A Ivana Chernykh Street, 198095 Saint Petersburg, Russia; (A.A.K.); (K.V.Z.)
| | - Kirill V. Zaichenko
- Laboratory of Radio- and Optoelectronic Devices for Early Diagnostics of Living Systems Pathologies, The Institute for Analytical Instrumentation, Russian Academy of Sciences, 31-33A Ivana Chernykh Street, 198095 Saint Petersburg, Russia; (A.A.K.); (K.V.Z.)
| | - Vladimir P. Shirinsky
- Institute of Experimental Cardiology Named after Academician V.N. Smirnov, National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia; (A.Y.K.); (M.V.S.); (M.E.P.); (O.A.K.); (V.P.S.)
| | - Michael M. Galagudza
- Institute of Experimental Medicine, Almazov National Medical Research Centre, 15B Parkhomenko Street, 194021 Saint Petersburg, Russia; (M.S.M.); (G.V.P.); (D.A.M.); (I.E.A.); (N.M.P.); (K.M.B.); (A.S.L.); (I.V.A.); (N.Y.S.); (M.M.G.)
- Laboratory of Radio- and Optoelectronic Devices for Early Diagnostics of Living Systems Pathologies, The Institute for Analytical Instrumentation, Russian Academy of Sciences, 31-33A Ivana Chernykh Street, 198095 Saint Petersburg, Russia; (A.A.K.); (K.V.Z.)
- Department of Pathophysiology with Clinical Pathophysiology Course, Pavlov First Saint Petersburg State Medical University, 6–8 Lev Tolstoy Street, 197022 Saint Petersburg, Russia
| |
Collapse
|
|
3
|
Zhao Y, Huang W, Liu F, Sun Q, Shen D, Fan W, Huang D, Zhang Y, Gao F, Wang B. Verapamil attenuates myocardial ischemia/reperfusion injury by inhibiting apoptosis via activating the JAK2/STAT3 signaling pathway. Biomed Pharmacother 2024; 180:117568. [PMID: 39405898 DOI: 10.1016/j.biopha.2024.117568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 11/14/2024] Open
Abstract
Apoptosis is a crucial pathological process in myocardial ischemia/reperfusion injury (MIRI). Verapamil (Ver), normally used to treat hypertension or heart rhythm disorders, also attenuates MIRI. The potential of Ver to inhibit apoptosis and thereby attenuate MIRI remains unclear, as does the mechanism. We established an in vivo mouse ischemia/reperfusion (I/R) model by occlusion of the left anterior descending coronary. To construct a hypoxia/reoxygenation model in vitro, H9c2 cardiomyocytes were immersed in a hypoxic buffer in a hypoxia/anaerobic workstation. Ver significantly improved cardiac function and reduced myocardial infarction size in I/R mice, while decreasing apoptosis. Both in vivo and in vitro, application of Ver activated the JAK2/STAT3 signaling pathway and elevated Bcl-2 expression, while decreasing Bax and cleaved caspase-3 levels. Treatment with AG490, a JAK2 inhibitor, partially counteracted the anti-apoptotic and the cardioprotective effect of Ver. Thus, we conclude that Ver alleviates MIRI by reducing apoptosis via the JAK2/STAT3 signaling pathway activation. These findings provide a novel mechanism of Ver in the treatment of MIRI.
Collapse
Affiliation(s)
- Yang Zhao
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Weiyi Huang
- Department of Clinical Pharmacy, Shantou University Medical College, Shantou 515041, China
| | - Fang Liu
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Qiang Sun
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Daifei Shen
- Research Center of Translational Medicine, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Wenjun Fan
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Danmei Huang
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Yanmei Zhang
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Fenfei Gao
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China
| | - Bin Wang
- Department of Pharmacology, Shantou University Medical College, Shantou 515041, China.
| |
Collapse
|
|
4
|
Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
Collapse
Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| |
Collapse
|
|
5
|
Al-Masri A. Apoptosis and long non-coding RNAs: Focus on their roles in Heart diseases. Pathol Res Pract 2023; 251:154889. [PMID: 38238070 DOI: 10.1016/j.prp.2023.154889] [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: 07/24/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 01/23/2024]
Abstract
Heart disease is one of the principal death reasons around the world and there is a growing requirement to discover novel healing targets that have the potential to avert or manage these illnesses. On the other hand, apoptosis is a strongly controlled, cell removal procedure that has a crucial part in numerous cardiac problems, such as reperfusion injury, MI (myocardial infarction), consecutive heart failure, and inflammation of myocardium. Completely comprehending the managing procedures of cell death signaling is critical as it is the primary factor that influences patient mortality and morbidity, owing to cardiomyocyte damage. Indeed, the prevention of heart cell death appears to be a viable treatment approach for heart illnesses. According to current researches, a number of long non-coding RNAs cause the heart cells death via different methods that are embroiled in controlling the activity of transcription elements, the pathways that signals transmission within cells, small miRNAs, and the constancy of proteins. When there is too much cell death in the heart, it can cause problems like reduced blood flow, heart damage after restoring blood flow, heart disease in diabetics, and changes in the heart after reduced blood flow. Therefore, studying how lncRNAs control apoptosis could help us find new treatments for heart diseases. In this review, we present recent discoveries about how lncRNAs are involved in causing cell death in different cardiovascular diseases.
Collapse
Affiliation(s)
- Abeer Al-Masri
- Department of Physiology, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
| |
Collapse
|
|
6
|
Pfeuffer AKM, Küpfer LK, Shankar TS, Drakos SG, Volk T, Seidel T. Ryanodine Receptor Staining Identifies Viable Cardiomyocytes in Human and Rabbit Cardiac Tissue Slices. Int J Mol Sci 2023; 24:13514. [PMID: 37686327 PMCID: PMC10488113 DOI: 10.3390/ijms241713514] [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: 08/06/2023] [Revised: 08/26/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
In terms of preserving multicellularity and myocardial function in vitro, the cultivation of beating myocardial slices is an emerging technique in basic and translational cardiac research. It can be used, for example, for drug screening or to study pathomechanisms. Here, we describe staining for viable cardiomyocytes based on the immunofluorescence of ryanodine receptors (RyRs) in human and rabbit myocardial slices. Biomimetic chambers were used for culture and measurements of contractile force. Fixable fluorophore-conjugated dextran, entering cells with a permeable membrane, was used for death staining. RyRs, nuclei and the extracellular matrix, including the t-system, were additionally stained and analyzed by confocal microscopy and image processing. We found the mutual exclusion of the RyR and dextran signals in cultivated slices. T-System density and nucleus size were reduced in RyR-negative/dextran-positive myocytes. The fraction of RyR-positive myocytes and pixels correlated with the contractile force. In RyR-positive/dextran-positive myocytes, we found irregular RyR clusters and SERCA distribution patterns, confirmed by an altered power spectrum. We conclude that RyR immunofluorescence indicates viable cardiomyocytes in vibratome-cut myocardial slices, facilitating the detection and differential structural analysis of living vs. dead or dying myocytes. We suggest the loss of sarcoplasmic reticulum integrity as an early event during cardiomyocyte death.
Collapse
Affiliation(s)
- Ann-Katrin M. Pfeuffer
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University (FAU) Erlangen-Nuremberg, 91054 Erlangen, Germany; (A.-K.M.P.); (L.K.K.); (T.V.)
| | - Linda K. Küpfer
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University (FAU) Erlangen-Nuremberg, 91054 Erlangen, Germany; (A.-K.M.P.); (L.K.K.); (T.V.)
| | - Thirupura S. Shankar
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; (T.S.S.); (S.G.D.)
| | - Stavros G. Drakos
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA; (T.S.S.); (S.G.D.)
| | - Tilmann Volk
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University (FAU) Erlangen-Nuremberg, 91054 Erlangen, Germany; (A.-K.M.P.); (L.K.K.); (T.V.)
| | - Thomas Seidel
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University (FAU) Erlangen-Nuremberg, 91054 Erlangen, Germany; (A.-K.M.P.); (L.K.K.); (T.V.)
| |
Collapse
|
|
7
|
Zeng JJ, Shi HQ, Ren FF, Zhao XS, Chen QY, Wang DJ, Wu LP, Chu MP, Lai TF, Li L. Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling. Acta Pharmacol Sin 2023; 44:1366-1379. [PMID: 36721009 PMCID: PMC10310839 DOI: 10.1038/s41401-023-01057-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 01/14/2023] [Indexed: 02/01/2023]
Abstract
Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30 min followed by 4 h reperfusion. The mice were treated with NG-R1 (25 mg/kg, i.p.) every 2 h for 3 times starting 30 min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25 μM) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor β-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.
Collapse
Affiliation(s)
- Jing-Jing Zeng
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
- Department of Cardiology, Ningbo No. 2 Hospital, Ningbo, 315000, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315000, China
| | - Han-Qing Shi
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Fang-Fang Ren
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiao-Shan Zhao
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Qiao-Ying Chen
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Dong-Juan Wang
- Department of Cardiology, Ningbo No. 2 Hospital, Ningbo, 315000, China
| | - Lian-Pin Wu
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Mao-Ping Chu
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Teng-Fang Lai
- Department of Cardiology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, China.
| | - Lei Li
- Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
| |
Collapse
|
|
8
|
Naseroleslami M, Sharifi M, Rakhshan K, Mokhtari B, Aboutaleb N. Nesfatin-1 attenuates injury in a rat model of myocardial infarction by targeting autophagy, inflammation, and apoptosis. Arch Physiol Biochem 2023; 129:122-130. [PMID: 32762481 DOI: 10.1080/13813455.2020.1802486] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nesfatin-1 plays an important role in the modulation of heart performance. However, it remains unclear how nesfatin-1 contributes to cell survival in acute myocardial infarction (MI). A rat model of MI was established via ligation of left anterior descending coronary artery (LAD) for 30 min and 20 µg/kg concentration of nesfatin-1 was intraperitoneally infused prior to reperfusion. At 24 h after reperfusion, oxidative stress markers, the expression of caspase3, beclin-1, pro-inflammatory cytokines, and the mRNA levels of Bax and Bcl-2 were evaluated. Results showed that nesfatin-1 markedly restored GSH content and SOD activity as well as reduced MDA levels compared to only the MI group (p < .05). Likewise, nesfatin-1 contributed to cell survival by inhibiting autophagy and apoptosis markers such as caspase3 and Bax (p < .05). Collectively, these findings support the idea that nasfatin-1 can be used as a good candidate to treat MI by targeting oxidative stress, apoptosis, and autophagy.
Collapse
Affiliation(s)
- Maryam Naseroleslami
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Masuomeh Sharifi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Kamran Rakhshan
- Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnaz Mokhtari
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nahid Aboutaleb
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
9
|
Horvath C, Kararigas G. Sex-Dependent Mechanisms of Cell Death Modalities in Cardiovascular Disease. Can J Cardiol 2022; 38:1844-1853. [PMID: 36152770 DOI: 10.1016/j.cjca.2022.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 12/14/2022] Open
Abstract
Despite currently available therapies, cardiovascular diseases (CVD) are among the leading causes of death globally. Biological sex is a critical determinant of the occurrence, progression and overall outcome of CVD. However, the underlying mechanisms are incompletely understood. A hallmark of CVD is cell death. Based on the inability of the human heart to regenerate, loss of functional cardiac tissue can lead to irreversible detrimental effects. Here, we summarize current knowledge on how biological sex affects cell death-related mechanisms in CVD. Initially, we discuss apoptosis and necrosis, but we specifically focus on the relatively newly recognized programmed necrosis-like processes: pyroptosis and necroptosis. We also discuss the role of 17β-estradiol (E2) in these processes, particularly in terms of inhibiting pyroptotic and necroptotic signaling. We put forward that a better understanding of the effects of biological sex and E2 might lead to the identification of novel targets with therapeutic potential.
Collapse
Affiliation(s)
- Csaba Horvath
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic
| | - Georgios Kararigas
- Department of Physiology, Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
| |
Collapse
|
|
10
|
Gu QL, Jiang P, Ruan HF, Tang H, Liang YB, Ma ZF, Zhan H. The expression of oxidative stress genes related to myocardial ischemia reperfusion injury in patients with ST-elevation myocardial infarction. World J Emerg Med 2022; 13:106-113. [PMID: 35237363 PMCID: PMC8861342 DOI: 10.5847/wjem.j.1920-8642.2022.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 12/20/2020] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND We aimed to investigate the gene expression of myocardial ischemia/reperfusion injury (MIRI) in patients with acute ST-elevation myocardial infarction (STEMI) using stress and toxicity pathway gene chip technology and try to determine the underlying mechanism. METHODS The mononuclear cells were separated by ficoll centrifugation, and plasma total antioxidant capacity (T-AOC) was determined by the ferric reducing ability of plasma (FRAP) assay. The expression of toxic oxidative stress genes was determined and verified by oligo gene chip and quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, gene ontology (GO) enrichment analysis was performed on DAVID website to analyze the potential mechanism further. RESULTS The total numbers of white blood cells (WBC) and neutrophils (N) in the peripheral blood of STEMI patients (the AMI group) were significantly higher than those in the control group (WBC: 11.67±4.85 ×109/L vs. 6.41±0.72 ×109/L, P<0.05; N: 9.27±4.75 ×109/L vs. 3.89±0.81 ×109/L, P<0.05), and WBCs were significantly associated with creatine kinase-myocardial band (CK-MB) on the first day (Y=8.945+0.018X, P<0.05). In addition, the T-AOC was significantly lower in the AMI group comparing to the control group (12.80±1.79 U/mL vs. 20.48±2.55 U/mL, P<0.05). According to the gene analysis, eight up-regulated differentially expressed genes (DEGs) included GADD45A, PRDX2, HSPD1, DNAJB1, DNAJB2, RAD50, TNFSF6, and TRADD. Four down-regulated DEGs contained CCNG1, CAT, CYP1A1, and ATM. TNFSF6 and CYP1A1 were detected by polymerase chain reaction (PCR) to verify the expression at different time points, and the results showed that TNFSF6 was up-regulated and CYP1A1 was down-regulated as the total expression. GO and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the oxidative stress genes mediate MIRI via various ways such as unfolded protein response (UPR) and apoptosis. CONCLUSIONS WBCs, especially neutrophils, were the critical cells that mediating reperfusion injury. MIRI was regulated by various genes, including oxidative metabolic stress, heat shock, DNA damage and repair, and apoptosis-related genes. The underlying pathway may be associated with UPR and apoptosis, which may be the novel therapeutic target.
Collapse
Affiliation(s)
- Qian-lin Gu
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Peng Jiang
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Hui-fen Ruan
- Huangpu District Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Hao Tang
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Yang-bing Liang
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Zhong-fu Ma
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Hong Zhan
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| |
Collapse
|
|
11
|
Ren Y, Lin S, Liu W, Ding H. Hepatic Remote Ischemic Preconditioning (RIPC) Protects Heart Damages Induced by Ischemia Reperfusion Injury in Mice. Front Physiol 2021; 12:713564. [PMID: 34671267 PMCID: PMC8520907 DOI: 10.3389/fphys.2021.713564] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/27/2021] [Indexed: 11/13/2022] Open
Abstract
It has been convincingly demonstrated that remote ischemic preconditioning (RIPC) can make the myocardium resistant to the subsequent ischemia reperfusion injury (IRI), which causes severe damages by mainly generating cell death. However, the cardioprotective effects of the hepatic RIPC, which is the largest metabolic organ against I/R, have not been fully studied. The aim of our research is whether remote liver RIPC may provide cardioprotective effects against the I/R-induced injury. Here, we generated an I/R mice model in four groups to analyze the effect. The control group is the isolated hearts with 140-min perfusion. I/R group added ischemia in 30 min following 90-min reperfusion. The third group (sham) was subjected to the same procedure as the latter group. The animals in the fourth group selected as the treatment group, underwent a hepatic RIPC by three cycles of 5-min occlusion of the portal triad and then followed by induction of I/R in the isolated heart. The level of myocardial infarction and the preventive effects of RIPC were assessed by pathological characteristics, namely, infarct, enzyme releases, pressure, and cardiac mechanical activity. Subjected to I/R, the hepatic RIPC minimized the infarct size (17.7 ± 4.96 vs. 50.06 ± 5, p < 0.001) and improved the left ventricular-developed pressure (from 47.42 ± 6.27 to 91.62 ± 5.22 mmHg) and the mechanical activity. Release of phosphocreatine kinase-myocardial band (73.86 ± 1.95 vs. 25.93 ± 0.66 IUL-1) and lactate dehydrogenase (299.01 ± 10.7 vs. 152.3 ± 16.7 IUL-1) was also decreased in the RIPC-treated group. These results demonstrate the cardioprotective effects of the hepatic remote preconditioning against the injury caused by I/R in the isolated perfused hearts.
Collapse
Affiliation(s)
- Yanlong Ren
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, China
| | - Shujin Lin
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Wenxian Liu
- Department of Cardiology, Beijing Anzhen Hospital, Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University, Beijing, China
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
12
|
Veres G, Bai Y, Stark KA, Schmidt H, Radovits T, Loganathan S, Korkmaz-Icöz S, Szabó G. Pharmacological activation of soluble guanylate cyclase improves vascular graft function. Interact Cardiovasc Thorac Surg 2021; 32:803-811. [PMID: 33515043 DOI: 10.1093/icvts/ivaa329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/26/2020] [Accepted: 11/06/2020] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Ischaemia-reperfusion injury impairs the nitric oxide/soluble guanylate cyclase/cyclic guanosine monophosphate (cGMP) signalling pathway and leads to vascular dysfunction. We assessed the hypothesis that the soluble guanylate cyclase activator cinaciguat would protect the vascular graft against ischaemia-reperfusion injury. METHODS In the treatment groups, rats (n = 8/group) were pretreated with either intravenous saline or intravenous cinaciguat (10 mg/kg) 2 h before an aortic transplant. Aortic grafts were stored for 2 h in saline and transplanted into the abdominal aorta of the recipients. Two hours after the transplant, the grafts were harvested and mounted in an organ bath. Vascular function of the grafts was investigated in the organ bath. Terminal deoxynucleotidyl transferase dUTP nick end labelling, cluster of differentiation 31, caspase-3, endothelial nitric oxide synthase, cGMP, nitrotyrosine and vascular cell adhesion molecule 1 immunochemical reactions were also investigated. RESULTS Pretreatment with cinaciguat significantly improved endothelium-dependent maximal relaxation 2 h after reperfusion compared with the saline group (maximal relaxation control: 96.5 ± 1%, saline: 40.4 ± 3% vs cinaciguat: 54.7 ± 2%; P < 0.05). Pretreatment with cinaciguat significantly reduced DNA fragmentation and nitro-oxidative stress; decreased the caspase-3 and vascular cell adhesion molecule 1 scores; and increased endothelial nitric oxide synthase, cGMP and cluster of differentiation 31 scores. CONCLUSIONS Our results demonstrated that enhancement of cGMP signalling by pharmacological activation of the soluble guanylate cyclase activator cinaciguat might represent a beneficial therapy for treating endothelial dysfunction of arterial bypass graft during cardiac surgery.
Collapse
Affiliation(s)
- Gábor Veres
- Department of Cardiac Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Yang Bai
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
| | - Klára Aliz Stark
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
| | - Harald Schmidt
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
| | | | - Sivakkanan Loganathan
- Department of Cardiac Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Sevil Korkmaz-Icöz
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
| | - Gábor Szabó
- Department of Cardiac Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
13
|
Chi Y, Peng B, Lu J. Effect of ovarian storage time at 4 degrees C on cumulus cell apoptosis in porcine antral follicles. Anim Sci J 2020; 91:e13465. [PMID: 33222358 DOI: 10.1111/asj.13465] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 07/08/2020] [Accepted: 07/15/2020] [Indexed: 02/03/2023]
Abstract
The present study was conducted to investigate the effect of cold storage time on apoptosis of cumulus cells (CCs) from porcine ovaries, and to compare the sensitivity of four apoptosis-detection methods. Porcine ovaries were stored in physiological saline solution at 4°C for 0, 7, 24 and 48 hr, and then cumulus cells or granulosa cells (GCs) in antral follicles were retrieved to detect cell apoptosis. Cumulus cells isolated from stored ovaries for 24 hr presented obvious apoptosis using terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP nick end-labeling (TUNEL) assay. A typical DNA ladder pattern of apoptosis was observed in GCs 24 hr post storage treatment. The mean Olive Tail Moment of CCs was significantly increased after 24 hr using comet assay; however, the mean tail migration and mean tail DNA increased gradually after 7 hr of storage. In addition, annexin V/PI staining assay showed an obvious increase in apoptotic CCs (Annexin V positive, PI negative) 7 hr after treatment, and the apoptotic rate reached to a peak at 24 hr followed by a decline after 48 hr of storage to the level at 7 hr. In conclusion, cold storage of porcine ovary in physiological saline solution induced a time-dependent increase in apoptosis of cumulus cells, and annexin V/PI staining combined with comet assay provided a sensitive and reliable method to detect early damages in cumulus cells induced by cold storage of ovary.
Collapse
Affiliation(s)
- Yafei Chi
- Laboratory Animal Center, Capital Medical University, Beijing, China
| | - Boya Peng
- Laboratory Animal Center, Capital Medical University, Beijing, China
| | - Jing Lu
- Laboratory Animal Center, Capital Medical University, Beijing, China.,Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing, China
| |
Collapse
|
|
14
|
Jiao L, Shao Y, Yu Q, Li M, Wang Y, Gong M, Yang X, Liu T, Li Z, Liu H, Zhang Y, Tan Z, Sun L, Xuan L, Yin H, Zhang Y, Cai B, Zhang Y, Yang B. GDF11 replenishment protects against hypoxia-mediated apoptosis in cardiomyocytes by regulating autophagy. Eur J Pharmacol 2020; 885:173495. [DOI: 10.1016/j.ejphar.2020.173495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 08/13/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
|
|
15
|
Wan X, Yao B, Ma Y, Liu Y, Tang Y, Hu J, Li M, Fu S, Zheng X, Yin D. MicroRNA-128-1-5p attenuates myocardial ischemia/reperfusion injury by suppressing Gadd45g-mediated apoptotic signaling. Biochem Biophys Res Commun 2020; 530:314-321. [PMID: 32828305 DOI: 10.1016/j.bbrc.2020.07.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/03/2020] [Indexed: 12/30/2022]
Abstract
Myocardial ischemia/reperfusion (I/R) injury is a clinically fatal disease, caused by restoring myocardial blood supply after a period of ischemia or hypoxia. However, the underlying mechanism remains unclear. Recently, increasing evidence reveal that microRNAs (miRs) participate in myocardial I/R injury. This study aimed to investigate whether miR-128-1-5p contributed to cardiomyocyte apoptosis induced by myocardial I/R injury. Here, we showed that the expression of miR-128-1-5p was decreased in mice following myocardial I/R injury. Down-regulation of miR-128-1-5p was also showed in H9c2 cardiomyocytes after hypoxia/reoxygenation (H/R), and in neonatal rat cardiomyocytes (NRCMs) with H2O2 treatment. Importantly, we found that overexpression of miR-128-1-5p ameliorates cardiomyocyte apoptosis both in H9c2 cardiomyocytes and NRCMs. Moreover, we also found that growth arrest DNA damage-inducible gene 45 gamma (Gadd45g) is identified as a direct target of miR-128-1-5p, which negatively regulated Gadd45g expression. Additionally, silencing of Gadd45g inhibits cardiomyocyte apoptosis in H9c2 cardiomyocytes and NRCMs. These results reveal a novel mechanism by which miR-128-1-5p regulates Gadd45g-mediated cardiomyocyte apoptosis in myocardial I/R injury.
Collapse
Affiliation(s)
- Xiaoya Wan
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Bifeng Yao
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Yeshuo Ma
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Yaxiu Liu
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Yao Tang
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Jia Hu
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Mingrui Li
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Shuang Fu
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Xinbin Zheng
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China
| | - Deling Yin
- Xiangya School of Pharmaceutical Science, Central South University, Changsha, Hunan, 41008, China; Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN, 37614, United States.
| |
Collapse
|
|
16
|
Liu TJ, Yeh YC, Lee WL, Wang LC, Lee HW, Shiu MT, Su CS, Lai HC. Insulin ameliorates hypoxia-induced autophagy, endoplasmic reticular stress and apoptosis of myocardial cells: In vitro and ex vivo models. Eur J Pharmacol 2020; 880:173125. [DOI: 10.1016/j.ejphar.2020.173125] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 04/15/2020] [Accepted: 04/20/2020] [Indexed: 12/16/2022]
|
|
17
|
Diazoxide Preconditioning of Nonhuman Primate Pancreas Improves Islet Isolation Outcomes by Mitochondrial Protection. Pancreas 2020; 49:706-713. [PMID: 32433410 DOI: 10.1097/mpa.0000000000001557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Previously, we showed that diazoxide (DZ), an effective ischemic preconditioning agent, protected rodent pancreas against ischemia-reperfusion injury. Here, we further investigate whether DZ supplementation to University of Wisconsin (UW) solution during pancreas procurement and islet isolation has similar cytoprotection in a preclinical nonhuman primate model. METHODS Cynomolgus monkey pancreata were flushed with UW or UW + 150 μM DZ during procurement and preserved for 8 hours before islet isolation. RESULTS First, a significantly higher islet yield was observed in UW + DZ than in UW (57,887 vs 23,574 IEq/pancreas and 5396 vs 1646 IEq/g). Second, the DZ treated islets had significantly lower apoptotic cells per islet (1.64% vs 9.85%). Third, DZ significantly inhibited ROS surge during reperfusion with a dose-response manner. Fourth, DZ improved in vitro function of isolated islets determined by mitochondrial potentials and calcium influx in responses to glucose and KCI. Fifth, the DZ treated islets had much higher cure rate and better glycemia control in diabetic mice transplant model. CONCLUSIONS This study showed a strong mitochondrial protection of DZ on nonhuman primate islets against ischemia-reperfusion injury that provides strong evidence for its clinical application in islet and pancreas transplantation.
Collapse
|
|
18
|
Tong G, Liang Y, Xue M, Chen X, Wang J, An N, Wang N, Chen Y, Wang Y, Jin L, Cong W. The protective role of bFGF in myocardial infarction and hypoxia cardiomyocytes by reducing oxidative stress via Nrf2. Biochem Biophys Res Commun 2020; 527:15-21. [PMID: 32446359 DOI: 10.1016/j.bbrc.2020.04.053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 04/12/2020] [Indexed: 01/30/2023]
Abstract
Myocardial infarction (MI) remains a major health-related problem with high incidence and mortality rates. Oxidative stress plays an important role in myocardial ischemia injury and further leads to myocardial remodeling. Basic fibroblast growth factor (bFGF) is a member of the fibroblast growth factors that regulate a variety of biological functions. However the function of bFGF in myocardial infarction is still unknown. Here we aimed to investigate the role of bFGF and its underlying mechanism in ischemia heart and cardiomyocytes apoptosis. We found that bFGF treatment could significantly enhance the cardioprotective effects by reducing oxidative stress both in vivo and vitro. In addition, we found that bFGF activated Nrf2-mediated antioxidant defenses via Akt/GSK3β/Fyn pathway. Furthermore, Nrf2 knockdown largely counteracted the protective effect of bFGF. In summary, our study suggested that bFGF could alleviate myocardial infarction injury and cardiomyocytes apoptosis via Nrf2.
Collapse
Affiliation(s)
- Gaozan Tong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | | | - Mei Xue
- Precision Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Xixi Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Jianan Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Ning An
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Nan Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Yunjie Chen
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Yang Wang
- Neuroscience Institute, Department of Histology and Embryology, Wenzhou Medical College, Wenzhou, Zhejiang, 325035, PR China.
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
| |
Collapse
|
|
19
|
Wang X, Chen J, Huang X. Rosuvastatin Attenuates Myocardial Ischemia-Reperfusion Injury via Upregulating miR-17-3p-Mediated Autophagy. Cell Reprogram 2019; 21:323-330. [PMID: 31730378 PMCID: PMC6918854 DOI: 10.1089/cell.2018.0053] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Myocardial diseases usually appear ischemic. Reperfusion therapy is one of the effective methods that can improve clinical therapeutic efficacy. However, reperfusion results in myocardial injury named I/R injury. Rosuvastatin (RS) is HMG-CoA reductase inhibitor. We investigated the role of RS in the myocardial I/R injury in vitro and its active mechanism. Oxygen-glucose deprivation/reoxygenation (OGD/R) model was applied to investigate I/R in vitro. OGD/R decreased cell viability and increased levels of miR-17-3p and lactate dehydrogenase (LDH) leakage. Besides, RS decreased cleaved caspase-3 level and LDH leakage, promoted the levels of miR-17-3p and LC3II/LC3I, and increased cell viability when H9C2 cell was treated by OGD/R. miR-17-3p inhibitor reduced the H9C2 cell viability and LC3II/LC3I level, whereas miR-17-3p mimics increased H9C2 cell viability and LC3II/LC3I level. RS promoted cell viability and increased LC3II/LC3I level while it lowered LDH leakage, apoptosis rate, and the levels of cleaved caspase-3 and Cyto c. Our study suggested that RS reduced I/R injury in cardiocyte via cleaved caspase-3/Cyto c apoptosis signaling pathway and autophagy. Moreover, the autophagy happens to cardiocyte by upregulating the expression of miR-17-3p.
Collapse
Affiliation(s)
- Xiaoqin Wang
- Department of Cardiovascular Medicine, Jingmen No.1 People's Hospital, Jingmen, China
| | - Jinghan Chen
- Department of Neurology, Jingmen Recovery Hospital, Jingmen, China
| | - Xiaojiao Huang
- Department of Cardiovascular Medicine, Jingmen No.1 People's Hospital, Jingmen, China
| |
Collapse
|
|
20
|
Xu W, Zhang L, Zhang Y, Zhang K, Wu Y, Jin D. TRAF1 Exacerbates Myocardial Ischemia Reperfusion Injury via ASK1-JNK/p38 Signaling. J Am Heart Assoc 2019; 8:e012575. [PMID: 31650881 PMCID: PMC6898833 DOI: 10.1161/jaha.119.012575] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background After acute myocardial infarction, the recovery of ischemic myocardial blood flow may cause myocardial reperfusion injury, which reduces the efficacy of myocardial reperfusion. Ways to reduce and prevent myocardial ischemia/reperfusion (I/R) injury are of great clinical significance in the treatment of patients with acute myocardial infarction. TRAF1 (tumor necrosis factor receptor-associated factor 1) is an important adapter protein that is implicated in molecular events regulating immunity, inflammation, and cell death. Little is known about the role and impact of TRAF1 in myocardial I/R injury. Methods and Results TRAF1 expression is markedly induced in wild-type mice and cardiomyocytes after I/R or hypoxia/reoxygenation stimulation. I/R models were established in TRAF1 knockout mice and wild type mice (n=10 per group). We demonstrated that TRAF1 deficiency protects against myocardial I/R-induced loss of heat function, inflammation, and cardiomyocyte death. In addition, overexpression of TRAF1 in primary cardiomyocytes promotes hypoxia/reoxygenation-induced inflammation and apoptosis in vitro. Mechanistically, TRAF1 promotes myocardial I/R injury through regulating ASK1 (apoptosis signal-regulating kinase 1)-mediated JNK/p38 (c-Jun N-terminal kinase/p38) MAPK (mitogen-activated protein kinase) cascades. Conclusions Our results indicated that TRAF1 aggravates the development of myocardial I/R injury by enhancing the activation of ASK1-mediated JNK/p38 cascades. Targeting the TRAF1-ASK1-JNK/p38 pathway provide feasible therapies for cardiac I/R injury.
Collapse
Affiliation(s)
- Weipan Xu
- Department of Cardiology Huangshi Central Hospital Affiliated Hospital of Hubei Polytechnic University Edong Healthcare Group Huang Shi China.,Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention Huang Shi China
| | - Li Zhang
- Center for Animal Experiment Wuhan University Wuhan China
| | - Yi Zhang
- Department of Cardiology Huangshi Central Hospital Affiliated Hospital of Hubei Polytechnic University Edong Healthcare Group Huang Shi China
| | - Kai Zhang
- Department of Cardiology Huangshi Central Hospital Affiliated Hospital of Hubei Polytechnic University Edong Healthcare Group Huang Shi China
| | - Yongbo Wu
- Department of Cardiology Huangshi Central Hospital Affiliated Hospital of Hubei Polytechnic University Edong Healthcare Group Huang Shi China
| | - Daoqun Jin
- Department of Cardiology Huangshi Central Hospital Affiliated Hospital of Hubei Polytechnic University Edong Healthcare Group Huang Shi China
| |
Collapse
|
|
21
|
Xue M, Joo YA, Li S, Niu C, Chen G, Yi X, Liang Y, Chen Z, Shen Y, Ye W, Cai L, Wang X, Jin L, Cong W. Metallothionein Protects the Heart Against Myocardial Infarction via the mTORC2/FoxO3a/Bim Pathway. Antioxid Redox Signal 2019; 31:403-419. [PMID: 30860395 DOI: 10.1089/ars.2018.7597] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Aims: Cardiac-specific overexpression of metallothionein (MT) has been shown to be beneficial in ischemic heart disease, but the detailed mechanisms through which MT protects against myocardial infarction (MI) remain unknown. This study assessed the involvement of the mTORC2/FoxO3a/Bim pathway in the cardioprotective effects of MT. Results: MI was induced in wild-type (FVB) mice and in cardiac-specific MT-overexpressing transgenic (MT-TG) mice by ligation of the left anterior descending (LAD) coronary artery. Cardiac function was better; infarct size and cardiomyocyte apoptosis were lower in MT-TG mice than in FVB mice after MI. Moreover, MT-TG mice exhibited better phenotypes after LAD ligation than FVB mice treated with Mn(III)tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; a reactive oxygen species [ROS] scavenger) and cardiac-specific catalase-overexpressing transgenic (CAT-TG) mice, which showed the same ROS levels as MT-TG mice after MI. Activation of mechanistic target of rapamycin complex 2 (mTORC2) was essential for the cardioprotective effects of MT against MI. In addition, MT attenuated the downregulation of phospho-FoxO3a after MI, inhibiting the expression of the apoptosis-associated gene Bim, located downstream of FoxO3a, and reducing the level of apoptosis after MI. To mimic ischemic-injured FVB and MT-TG mice in vitro, H9c2 and MT-overexpressing H9c2 (H9c2MT7) cardiomyocytes were subjected to oxygen and glucose deprivation, with the results being consistent with those obtained in vivo. Innovation and Conclusion: The cardioprotective effects of MT against MI are not entirely dependent upon its ability to eliminate ROS. Rather, MT overexpression mostly protects against MI through the mTORC2-FoxO3a-Bim pathway.
Collapse
Affiliation(s)
- Mei Xue
- 1 Precision Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Young A Joo
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Santie Li
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Chao Niu
- 3 The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Gen Chen
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xinchu Yi
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yangzhi Liang
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zhiwei Chen
- 3 The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yingjie Shen
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Weijian Ye
- 3 The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Lu Cai
- 4 Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, Kentucky
| | - Xu Wang
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Litai Jin
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Weitao Cong
- 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, People's Republic of China
| |
Collapse
|
|
22
|
Saad NS, Elnakish MT, Ahmed AAE, Janssen PML. Protein Kinase A as a Promising Target for Heart Failure Drug Development. Arch Med Res 2018; 49:530-537. [PMID: 30642654 PMCID: PMC6451668 DOI: 10.1016/j.arcmed.2018.12.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 12/13/2018] [Indexed: 12/24/2022]
Abstract
Heart failure (HF) is a clinical syndrome characterized by impaired ability of the heart to fill or eject blood. HF is rather prevalent and it represents the foremost reason of hospitalization in the United States. The costs linked to HF overrun those of all other causes of disabilities, and death in the United States and all over the developed as well as the developing countries which amplify the supreme significance of its prevention. Protein kinase (PK) A plays multiple roles in heart functions including, contraction, metabolism, ion fluxes, and gene transcription. Altered PKA activity is likely to cause the progression to cardiomyopathy and HF. Thus, this review is intended to focus on the roles of PKA and PKA-mediated signal transduction in the healthy heart as well as during the development of HF. Furthermore, the impact of cardiac PKA inhibition/activation will be highlighted to identify PKA as a potential target for the HF drug development.
Collapse
Affiliation(s)
- Nancy S Saad
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Mohammad T Elnakish
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Amany A E Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Paul M L Janssen
- Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
| |
Collapse
|
|
23
|
Vairamani K, Prasad V, Wang Y, Huang W, Chen Y, Medvedovic M, Lorenz JN, Shull GE. NBCe1 Na +-HCO3 - cotransporter ablation causes reduced apoptosis following cardiac ischemia-reperfusion injury in vivo. World J Cardiol 2018; 10:97-109. [PMID: 30344957 PMCID: PMC6189072 DOI: 10.4330/wjc.v10.i9.97] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 07/05/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na+-HCO3- cotransporter is cardioprotective during in vivo ischemia-reperfusion (IR) injury.
METHODS An NBCe1 (Slc4a4 gene) conditional knockout mouse (KO) model was prepared by gene targeting. Cardiovascular performance of wildtype (WT) and cardiac-specific NBCe1 KO mice was analyzed by intraventricular pressure measurements, and changes in cardiac gene expression were determined by RNA Seq analysis. Response to in vivo IR injury was analyzed after 30 min occlusion of the left anterior descending artery followed by 3 h of reperfusion.
RESULTS Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation under basal conditions or in response to β-adrenergic stimulation, and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections.
CONCLUSION These studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against IR injury in vivo .
Collapse
Affiliation(s)
- Kanimozhi Vairamani
- Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3026, United States
| | - Vikram Prasad
- Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229-3039, United States
| | - Yigang Wang
- Department of Pathology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0529, United States
| | - Wei Huang
- Department of Pathology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0529, United States
| | - Yinhua Chen
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, United States
| | - Mario Medvedovic
- Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0056, United States
| | - John N Lorenz
- Department of Pharmacology and Systems Physiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0575, United States
| | - Gary E Shull
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0524, United States
| |
Collapse
|
|
24
|
Postischemic application of estrogen ameliorates myocardial damage in an in vivo mouse model. J Surg Res 2018; 231:366-372. [PMID: 30278955 DOI: 10.1016/j.jss.2018.05.076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/27/2018] [Accepted: 05/31/2018] [Indexed: 02/02/2023]
Abstract
BACKGROUND Cardioprotection provided by estrogen has been recognized for many years. It is noteworthy that most of these studies employ a means of preinjury application in experimental research and the preventive usage in clinical studies. Compared to pretreatment, postischemic administration of estrogen will be more practical in treating myocardial ischemia. On the other hand, defect in circadian clock gene period2 (Per2) has been shown to aggravate ischemia-induced heart damage. Given that Per2 expression decreases as a consequence of menopause, in this study, we aim to determine (1) potential improvement of myocardial function by postischemic administration of 17β-estradiol (E2) using an in vivo mouse myocardial ischemia/reperfusion (I/R) model and (2) the role of E2 in regulating myocardial Per2 expression following I/R. METHODS Thirty-minute occlusion of left anterior descending artery followed by 24-h reperfusion was performed on adult C57BL ovariectomized female mice. Groups (n = 3-6/group) were as follows: (1) Sham, (2) I/R + vehicle, and (3) I/R + E2. Vehicle or 0.5 mg/kg of E2 was subcutaneously injected right after 30-min ischemia. Following 24-h reperfusion, myocardial function was determined. Heart tissue was collected for analysis of cleaved caspase-3 and Per2 expression by Western blotting, as well as proinflammatory cytokine production (IL-1β, IL-6, and TNF-α) by enzyme-linked immunosorbent assay. RESULTS I/R significantly impaired left ventricular function and increased myocardial levels of active caspase-3, IL-1β, and IL-6. Importantly, postischemic treatment of E2 markedly restored I/R-depressed myocardial function, reduced caspase-3 activation, and decreased proinflammatory cytokine production (IL-1β, IL-6, and TNF-α). Intriguingly, a trend of the decreased Per2 level was observed in ovariectomized female hearts subjected to I/R, whereas E2 treatment upregulated myocardial Per2 expression. CONCLUSIONS Our study represents the initial evidence that postischemic administration of E2 effectively preserves the myocardium against I/R injury and this protective effect of E2 may involve upregulation of Per2 in ischemic heart.
Collapse
|
|
25
|
Wang LQ, He Y, Wan HF, Zhou HF, Yang JH, Wan HT. Protective mechanisms of hypaconitine and glycyrrhetinic acid compatibility in oxygen and glucose deprivation injury. J Zhejiang Univ Sci B 2018; 18:586-596. [PMID: 28681583 DOI: 10.1631/jzus.b1600270] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
This study investigated the protective effect of the compatibility of hypaconitine (HA) and glycyrrhetinic acid (GA) on H9c2 cells under oxygen and glucose deprivation (OGD)-induced injury, and the possible mechanisms. We found that HA+GA significantly improved pathology and morphology of the nucleus and ultrastructure of H9c2 cells under OGD as determined by Hoechst 33342 staining and transmission electron microscopy (TEM) tests. It also reduced the releases of lactate dehydrogenase (LDH), creatine kinase-myocardial band isoenzyme (CK-MB), and aspartate transaminase (AST) from the cultured supernatant of H9c2 cells, which were tested by enzyme-linked immune sorbent assay (ELISA) kits. In addition, it lessened the apoptotic rate as determined by a fluorescein isothiocyanate-annexin V/propidium iodide (FITC-AV/PI) double staining assay. It was also found that HA+GA might regulate the protein expression associated with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Overall, the study demonstrated that HA+GA protected H9c2 cells against OGD-induced injury, and the signaling mechanism might be related to the PI3K/Akt signaling pathway.
Collapse
Affiliation(s)
- Li-Qin Wang
- Cardio-Cerebro Vascular Research Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yu He
- Cardio-Cerebro Vascular Research Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Hao-Fang Wan
- Cardio-Cerebro Vascular Research Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Hui-Fen Zhou
- Cardio-Cerebro Vascular Research Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jie-Hong Yang
- Cardio-Cerebro Vascular Research Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Hai-Tong Wan
- Cardio-Cerebro Vascular Research Institute, Zhejiang Chinese Medical University, Hangzhou 310053, China
| |
Collapse
|
|
26
|
β-adrenergic Receptor-stimulated Cardiac Myocyte Apoptosis: Role of Cytochrome P450 ω-hydroxylase. J Cardiovasc Pharmacol 2018; 70:94-101. [PMID: 28768289 DOI: 10.1097/fjc.0000000000000499] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Prolonged or excessive β-adrenergic activation leads to cardiac myocyte loss and heart dysfunction; however, the underlying cellular mechanisms are still unclear. Therefore, we first confirmed the effect of isoproterenol (ISO), a β-adrenergic receptor agonist, on cardiac toxicity using TUNEL and caspase activity assays in cultured rat cardiomyocytes. ISO treatment significantly increased cardiomyocyte apoptosis. Persistent ISO stimulation of cardiomyocytes also increased the expression of CYP4A3, a major CYP450 ω-hydroxylase that produces 20-hydroxyeicosatetraenoic acid (20-HETE) in a time-dependent manner. Next, we examined the effect of ISO and 20-HETE on cardiomyocyte apoptosis using annexin V and propidium iodide staining. Treatment with either 20-HETE or ISO significantly increased cardiomyocyte apoptosis, and inhibition of 20-HETE production using 17-ODYA, a CYP450 ω-hydroxylase inhibitor, dramatically attenuated ISO-induced cardiomyocyte apoptosis. To determine the apoptotic pathway involved, the mitochondrial membrane potential (ΔΨm) was measured by detecting the ratio of JC-1 green/red emission intensity. The results demonstrated that 17-ODYA significantly abolished ISO-induced disruption of ΔΨm and that 20-HETE alone induced a marked disruptive effect on ΔΨm in cardiomyocytes. In addition, 20-HETE-induced disruption of ΔΨm and apoptosis was significantly attenuated by KN93, a CaMKII inhibitor. Taken together, these results demonstrate that 20-HETE treatment induces significant apoptosis via mitochondrial-dependent pathways, and that inhibition of 20-HETE production using 17-ODYA attenuates ISO-induced cardiomyocyte apoptosis.
Collapse
|
|
27
|
Rybczynska AA, Boersma HH, de Jong S, Gietema JA, Noordzij W, Dierckx RAJO, Elsinga PH, van Waarde A. Avenues to molecular imaging of dying cells: Focus on cancer. Med Res Rev 2018. [PMID: 29528513 PMCID: PMC6220832 DOI: 10.1002/med.21495] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Successful treatment of cancer patients requires balancing of the dose, timing, and type of therapeutic regimen. Detection of increased cell death may serve as a predictor of the eventual therapeutic success. Imaging of cell death may thus lead to early identification of treatment responders and nonresponders, and to “patient‐tailored therapy.” Cell death in organs and tissues of the human body can be visualized, using positron emission tomography or single‐photon emission computed tomography, although unsolved problems remain concerning target selection, tracer pharmacokinetics, target‐to‐nontarget ratio, and spatial and temporal resolution of the scans. Phosphatidylserine exposure by dying cells has been the most extensively studied imaging target. However, visualization of this process with radiolabeled Annexin A5 has not become routine in the clinical setting. Classification of death modes is no longer based only on cell morphology but also on biochemistry, and apoptosis is no longer found to be the preponderant mechanism of cell death after antitumor therapy, as was earlier believed. These conceptual changes have affected radiochemical efforts. Novel probes targeting changes in membrane permeability, cytoplasmic pH, mitochondrial membrane potential, or caspase activation have recently been explored. In this review, we discuss molecular changes in tumors which can be targeted to visualize cell death and we propose promising biomarkers for future exploration.
Collapse
Affiliation(s)
- Anna A Rybczynska
- Molecular Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Department of Genetics, University of Groningen, Groningen, the Netherlands
| | - Hendrikus H Boersma
- Molecular Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Department of Clinical Pharmacy & Pharmacology, University of Groningen, Groningen, the Netherlands
| | - Steven de Jong
- Department of Medical Oncology, University of Groningen, Groningen, the Netherlands
| | - Jourik A Gietema
- Department of Medical Oncology, University of Groningen, Groningen, the Netherlands
| | - Walter Noordzij
- Molecular Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Rudi A J O Dierckx
- Molecular Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Department of Nuclear Medicine, Ghent University, Ghent, Belgium
| | - Philip H Elsinga
- Molecular Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Aren van Waarde
- Molecular Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| |
Collapse
|
|
28
|
Aljakna A, Fracasso T, Sabatasso S. Molecular tissue changes in early myocardial ischemia: from pathophysiology to the identification of new diagnostic markers. Int J Legal Med 2018; 132:425-438. [DOI: 10.1007/s00414-017-1750-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/20/2017] [Indexed: 02/06/2023]
|
|
29
|
Molecular mechanism of doxorubicin-induced cardiomyopathy - An update. Eur J Pharmacol 2017; 818:241-253. [PMID: 29074412 DOI: 10.1016/j.ejphar.2017.10.043] [Citation(s) in RCA: 388] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/11/2017] [Accepted: 10/20/2017] [Indexed: 12/27/2022]
Abstract
Doxorubicin is utilized for anti-neoplastic treatment for several decades. The utility of this drug is limited due to its side effects. Generally, doxorubicin toxicity is originated from the myocardium and then other organs are also ruined. The mechanism of doxorubicin is intercalated with the DNA and inhibits topoisomerase 2. There are various signalling mechanisms involved in doxorubicin cardiotoxicity. First and foremost, the doxorubicin-induced cardiotoxicity is due to oxidative stress. Cardiac mitochondrial damage is supposed after few hours following the revelation of doxorubicin. This has led important new uses for the mechanism of doxorubicin-induced cardiotoxicity and novel avenues of investigation to determine better pharmacotherapies and interventions for the impediment of cardiotoxicity. The idea of this review is to bring up to date the recent findings of the mechanism of doxorubicin cardiomyopathies such as calcium dysregulation, endoplasmic reticulum stress, impairment of progenitor cells, activation of immune, ubiquitous system and some other parameters.
Collapse
|
|
30
|
Li Y, Jiang T, Fu X, Xu H, Ji J. Atorvastatin protects cardiomyocytes against OGD/R‑induced apoptosis by inhibiting miR‑199a‑5p. Mol Med Rep 2017; 16:3807-3816. [PMID: 28765953 PMCID: PMC5646958 DOI: 10.3892/mmr.2017.7084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 05/12/2017] [Indexed: 11/21/2022] Open
Abstract
The present study aimed to evaluate the protective effects of atorvastatin against myocardial ischemia/reperfusion (I/R) injury in cardiomyocytes and its underlying mechanisms. The direct cytotoxic effects of oxygen-glucose deprivation/reperfusion (OGD/R) on cardiomyocytes with and without atorvastatin pretreatment were evaluated. The effects of atorvastatin on the expression of glycogen synthase kinase-3β (GSK-3β) and microRNA (miR)-199a-5p were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses. In addition, the expression levels of GSK-3β in cells with miR-199a-5p upregulation and downregulation were detected using RT-qPCR, western blot and immunohistochemical analyses. Pretreatment with atorvastatin significantly improved the recovery of cell viability from OGD/R (P<0.05). In addition, atorvastatin pretreatment significantly increased the expression of GSK-3β at the mRNA and protein levels, and the expression of miR-199a-5p at the mRNA level (all P<0.05). The upregulation and downregulation of miR-199a-5p respectively decreased and increased the expression of GSK-3β at the mRNA and protein levels. These results suggested that atorvastatin provided cardioprotective effects against I/R injury via increasing the expression of GSK-3β through the inhibition of miR-199a-5p.
Collapse
Affiliation(s)
- Yong Li
- Department of Cardiology, The Affiliated Wujin Hospital of Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
| | - Ting Jiang
- Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xingli Fu
- Health Science Center of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Hao Xu
- Department of Cardiology, The Affiliated Wujin Hospital of Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
| | - Jianguo Ji
- Department of Cardiology, The Affiliated Wujin Hospital of Jiangsu University, Changzhou, Jiangsu 213017, P.R. China
| |
Collapse
|
|
31
|
Adameova A, Hrdlicka J, Szobi A, Farkasova V, Kopaskova K, Murarikova M, Neckar J, Kolar F, Ravingerova T, Dhalla NS. Evidence of necroptosis in hearts subjected to various forms of ischemic insults. Can J Physiol Pharmacol 2017; 95:1163-1169. [PMID: 28472590 DOI: 10.1139/cjpp-2016-0609] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Long-lasting ischemia can result in cell loss; however, repeated episodes of brief ischemia increase the resistance of the heart against deleterious effects of subsequent prolonged ischemic insult and promote cell survival. Traditionally, it is believed that the supply of blood to the ischemic heart is associated with release of cytokines, activation of inflammatory response, and induction of necrotic cell death. In the past few years, this paradigm of passive necrosis as an uncontrolled cell death has been re-examined and the existence of a strictly regulated form of necrotic cell death, necroptosis, has been documented. This controlled cell death modality, resembling all morphological features of necrosis, has been investigated in different types of ischemia-associated heart injuries. The process of necroptosis has been found to be dependent on the activation of RIP1-RIP3-MLKL axis, which induces changes leading to the rupture of cell membrane. This pathway is activated by TNF-α, which has also been implicated in the cardioprotective signaling pathway of ischemic preconditioning. Thus, this review is intended to describe the TNF-α-mediated signaling leading to either cell survival or necroptotic cell death. In addition, some experimental data suggesting a link between heart dysfunction and the cellular loss due to necroptosis are discussed in various conditions of myocardial ischemia.
Collapse
Affiliation(s)
- Adriana Adameova
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic
| | - Jaroslav Hrdlicka
- b Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Adrian Szobi
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic
| | - Veronika Farkasova
- c Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence, SAS NOREG, Bratislava, Slovak Republic
| | - Katarina Kopaskova
- a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic
| | - Martina Murarikova
- c Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence, SAS NOREG, Bratislava, Slovak Republic
| | - Jan Neckar
- b Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Frantisek Kolar
- b Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - Tatiana Ravingerova
- c Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence, SAS NOREG, Bratislava, Slovak Republic
| | - Naranjan S Dhalla
- d Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| |
Collapse
|
|
32
|
Aqueous extract of Cortex Dictamni protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress and apoptosis by PI3K/Akt signaling pathway. Biomed Pharmacother 2017; 89:233-244. [DOI: 10.1016/j.biopha.2017.02.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 02/07/2017] [Accepted: 02/07/2017] [Indexed: 12/13/2022] Open
|
|
33
|
Chagtoo M, George N, Pathak N, Tiwari S, Godbole MM, Ladilov Y. Inhibition of Intracellular Type 10 Adenylyl Cyclase Protects Cortical Neurons Against Reperfusion-Induced Mitochondrial Injury and Apoptosis. Mol Neurobiol 2017; 55:2471-2482. [PMID: 28386847 DOI: 10.1007/s12035-017-0473-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 02/24/2017] [Indexed: 02/07/2023]
Abstract
Mitochondrial injury significantly contributes to the neuronal death under cerebral ischemia and reperfusion. Within several signaling pathways, cyclic adenosine monophosphate (cAMP) signaling plays a substantial role in mitochondrial injury and cell death. Traditionally, the source of cellular cAMP has been attributed to the membrane-bound adenylyl cyclase, whereas the role of the intracellular localized type 10 soluble adenylyl cyclase (sAC) in neuronal pathology has not been considered. Since neurons express an active form of sAC, we aimed to investigate the role of sAC in reperfusion-induced neuronal apoptosis. For this purpose, the in vitro model of oxygen/glucose deprivation (simulated ischemia, 1 h), followed by recovery (simulated reperfusion, 12 h) in rat embryonic neurons, was applied. Although ischemia alone had no significant effect on apoptosis, reperfusion led to an activation of the mitochondrial pathway of apoptosis, hallmarked by mitochondrial depolarization, cytochrome c release, and mitochondrial ROS formation. These effects were accompanied by significantly augmented sAC expression and increased cellular cAMP content during reperfusion. Pharmacological suppression of sAC during reperfusion reduced cellular cAMP and ameliorated reperfusion-induced mitochondrial apoptosis and ROS formation. Similarly, sAC knockdown prevented neuronal death. Further analysis revealed a role of protein kinase A (PKA), a major downstream target of sAC, in reperfusion-induced neuronal apoptosis and ROS formation. In conclusion, the results show a causal role of intracellular, sAC-dependent cAMP signaling in reperfusion-induced mitochondrial injury and apoptosis in neurons. The protective effect of sAC inhibition during the reperfusion phase provides a basis for the development of new strategies to prevent the reperfusion-induced neuronal injury.
Collapse
Affiliation(s)
- Megha Chagtoo
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.,Department of Bioscience, Integral University, Lucknow, India
| | - Nelson George
- Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Neelam Pathak
- Department of Bioscience, Integral University, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Madan M Godbole
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Yury Ladilov
- Department of Clinical Pharmacology, Ruhr University Bochum, Bochum, Germany. .,Center for Cardiovascular Research, Charité-Mitte, Hessische Strasse 3-4, 10115, Berlin, Germany.
| |
Collapse
|
|
34
|
Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart. J Physiol Biochem 2017; 73:323-333. [PMID: 28258543 PMCID: PMC5534207 DOI: 10.1007/s13105-017-0555-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 02/10/2017] [Indexed: 01/11/2023]
Abstract
Ischemia/reperfusion (I/R) of the heart becomes injurious when duration of the ischemic insult exceeds a certain threshold (approximately ≥20 min). Mitochondrial bound hexokinase II (mtHKII) protects against I/R injury, with the amount of mtHKII correlating with injury. Here, we examine whether mtHKII can induce the transition from non-injurious to injurious I/R, by detaching HKII from mitochondria during a non-injurious I/R interval. Additionally, we examine possible underlying mechanisms (increased reactive oxygen species (ROS), increased oxygen consumption (MVO2) and decreased cardiac energetics) associated with this transition. Langendorff perfused rat hearts were treated for 20 min with saline, TAT-only or 200 nM TAT-HKII, a peptide that translocates HKII from mitochondria. Then, hearts were exposed to non-injurious 15-min ischemia, followed by 30-min reperfusion. I/R injury was determined by necrosis (LDH release) and cardiac mechanical recovery. ROS were measured by DHE fluorescence. Changes in cardiac respiratory activity (cardiac MVO2 and efficiency and mitochondrial oxygen tension (mitoPO2) using protoporphyrin IX) and cardiac energetics (ATP, PCr, ∆GATP) were determined following peptide treatment. When exposed to 15-min ischemia, control hearts had no necrosis and 85% recovery of function. Conversely, TAT-HKII treatment resulted in significant LDH release and reduced cardiac recovery (25%), indicating injurious I/R. This was associated with increased ROS during ischemia and reperfusion. TAT-HKII treatment reduced MVO2 and improved energetics (increased PCr) before ischemia, without affecting MVO2/RPP ratio or mitoPO2. In conclusion, a reduction in mtHKII turns non-injurious I/R into injurious I/R. Loss of mtHKII was associated with increased ROS during ischemia and reperfusion, but not with increased MVO2 or decreased cardiac energetics before damage occurs.
Collapse
|
|
35
|
Ischemia/Reperfusion Injury following Acute Myocardial Infarction: A Critical Issue for Clinicians and Forensic Pathologists. Mediators Inflamm 2017; 2017:7018393. [PMID: 28286377 PMCID: PMC5327760 DOI: 10.1155/2017/7018393] [Citation(s) in RCA: 274] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 10/26/2016] [Accepted: 11/30/2016] [Indexed: 12/27/2022] Open
Abstract
Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality. Reperfusion strategies are the current standard therapy for AMI. However, they may result in paradoxical cardiomyocyte dysfunction, known as ischemic reperfusion injury (IRI). Different forms of IRI are recognized, of which only the first two are reversible: reperfusion-induced arrhythmias, myocardial stunning, microvascular obstruction, and lethal myocardial reperfusion injury. Sudden death is the most common pattern for ischemia-induced lethal ventricular arrhythmias during AMI. The exact mechanisms of IRI are not fully known. Molecular, cellular, and tissue alterations such as cell death, inflammation, neurohumoral activation, and oxidative stress are considered to be of paramount importance in IRI. However, comprehension of the exact pathophysiological mechanisms remains a challenge for clinicians. Furthermore, myocardial IRI is a critical issue also for forensic pathologists since sudden death may occur despite timely reperfusion following AMI, that is one of the most frequently litigated areas of cardiology practice. In this paper we explore the literature regarding the pathophysiology of myocardial IRI, focusing on the possible role of the calpain system, oxidative-nitrosative stress, and matrix metalloproteinases and aiming to foster knowledge of IRI pathophysiology also in terms of medicolegal understanding of sudden deaths following AMI.
Collapse
|
|
36
|
Novel protective effects of pulsed electromagnetic field ischemia/reperfusion injury rats. Biosci Rep 2016; 36:BSR20160082. [PMID: 27780890 PMCID: PMC5137536 DOI: 10.1042/bsr20160082] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 10/11/2016] [Accepted: 10/17/2016] [Indexed: 01/02/2023] Open
Abstract
Pulsed electromagnetic field (PEMF) treatment protected ischaemia/reperfusion (I/R) injury from apoptosis via B-cell lymphoma 2 (Bcl-2), Bax and nitric oxide (NO) releasing. Extracorporeal pulsed electromagnetic field (PEMF) has shown the ability to regenerate tissue by promoting cell proliferation. In the present study, we investigated for the first time whether PEMF treatment could improve the myocardial ischaemia/reperfusion (I/R) injury and uncovered its underlying mechanisms. In our study, we demonstrated for the first time that extracorporeal PEMF has a novel effect on myocardial I/R injury. The number and function of circulating endothelial progenitor cells (EPCs) were increased in PEMF treating rats. The in vivo results showed that per-treatment of PEMF could significantly improve the cardiac function in I/R injury group. In addition, PEMF treatment also reduced the apoptosis of myocardial cells by up-regulating the expression of anti-apoptosis protein B-cell lymphoma 2 (Bcl-2) and down-regulating the expression of pro-apoptosis protein (Bax). In vitro, the results showed that PEMF treatment could significantly reduce the apoptosis and reactive oxygen species (ROS) levels in primary neonatal rat cardiac ventricular myocytes (NRCMs) induced by hypoxia/reoxygenation (H/R). In particular, PEMF increased the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS), which might be closely related to attenuated cell apoptosis by increasing the releasing of nitric oxide (NO). Therefore, our data indicated that PEMF could be a potential candidate for I/R injury.
Collapse
|
|
37
|
Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury. J Physiol Biochem 2016; 73:111-120. [PMID: 27771871 DOI: 10.1007/s13105-016-0530-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Accepted: 10/12/2016] [Indexed: 12/15/2022]
Abstract
It has been shown that diabetes modifies the myocardial responses to ischemia/reperfusion (I/R) and to cardioprotective agents. In this study, we aimed to investigate the effects of combined treatment with ischemic postconditioning (IPostC) and cyclosporine A (CsA) on inflammation and apoptosis of the diabetic myocardium injured by I/R. Eight weeks after induction of diabetes in Wistar rats, hearts were mounted on a Langendorff apparatus and were subsequently subjected to a 30-min regional ischemia followed by 45-min reperfusion. IPostC was induced at the onset of reperfusion, by 3 cycles of 30-s reperfusion/ischemia (R/I). The concentration of creatine kinase (CK), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined; the levels of total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β) and B-cell lymphoma 2 (Bcl-2) were quantified by western blotting, and the rate of apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Administration of either IPostC or CsA alone in nondiabetic animals significantly reduced CK, TNF-α, IL-1β, and IL-6 concentrations, increased the p-GSK3β and Bcl-2, and decreased the level of apoptosis (P < 0.05) but had no effect on diabetic hearts. However, in diabetic animals, after administration of CsA, the cardioprotective effects of IPostC in increasing the p-GSK3β and Bcl-2 and decreasing apoptosis and inflammation were restored in comparison with nonpostconditioned diabetic hearts. IPostC or CsA failed to affect apoptosis and inflammation and failed to protect the diabetic myocardium against I/R injury. However, combined administration of IPostC and CsA at reperfusion can protect the diabetic myocardium by decreasing the inflammatory response and apoptosis.
Collapse
|
|
38
|
GE ZHIRU, XU MAOCHUN, HUANG YU, ZHANG CHENJUN, LIN JE, RUAN CHANGWU. Cardioprotective effect of notoginsenoside R1 in a rabbit lung remote ischemic postconditioning model via activation of the TGF-β1/TAK1 signaling pathway. Exp Ther Med 2016; 11:2341-2348. [PMID: 27284318 PMCID: PMC4887923 DOI: 10.3892/etm.2016.3222] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 01/11/2016] [Indexed: 12/29/2022] Open
Abstract
Pharmacological postconditioning using cardioprotective agents is able to reduce myocardial infarct size. Notoginsenoside R1 (NG-R1), a phytoestrogen isolated from Panax notoginseng saponins (PNS), is considered to have anti-oxidative and anti-apoptotic properties. However, its cardioprotective properties and underlying mechanisms remain largely unknown. The aim of the present study was to determine the cardioprotective and anti-apoptotic effects of NG-R1 in an ischemia-reperfusion (IR)-induced myocardial injury rabbit model. A total of 45 Japanese big-ear rabbits were equally randomized to three groups: Control group, remote ischemic postconditioning (RIP) group and NG-R1 intervention group. At the endpoint of the experiment, the animals were sacrificed to remove myocardial tissues for the detection of transforming growth factor (TGF)-β1-TGF-β activated kinase 1 (TAK1) pathway-related proteins by immunohistochemistry and western blot analysis, the activities of caspase-3, -8 and -9 in myocardial cells by fluorometric assay, and the apoptosis of myocardial cells by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling. Right and left lung tissues were stained with hematoxylin and eosin (H&E) to observe the severity of injury. NG-R1 treatment reduced the activity of superoxide dismutase, increased the content of malondialdehyde, reduced the activities of caspase-3, -8 and -9, and inhibited the apoptosis of myocardial cells in rabbits undergoing RIP. In addition, the expression of TGF-β1-TAK1 signaling pathway-related proteins was downregulated following NG-R1 intervention. H&E staining of bilateral lung tissues showed that cell morphology was generally intact without significant alveolar congestion, and there was no significant difference among the three groups. These results indicate that NG-R1 protects the heart against IR injury, possibly by inhibiting the activation of the TGF-β1-TAK1 signaling pathway and attenuating apoptotic stress in the myocardium.
Collapse
Affiliation(s)
- ZHI-RU GE
- Department of Cardiology, Shanghai Pudong New Area Gongli Hospital, Shanghai 200135, P.R. China
| | - MAO-CHUN XU
- Department of Cardiology, Shanghai Pudong New Area Gongli Hospital, Shanghai 200135, P.R. China
| | - YU HUANG
- Department of Cardiology, Shanghai Pudong New Area Gongli Hospital, Shanghai 200135, P.R. China
| | - CHEN-JUN ZHANG
- Department of Cardiology, Shanghai Pudong New Area Gongli Hospital, Shanghai 200135, P.R. China
| | - JE LIN
- Department of Cardiology, Shanghai Pudong New Area Gongli Hospital, Shanghai 200135, P.R. China
| | - CHANG-WU RUAN
- Department of Cardiology, Shanghai Pudong New Area Gongli Hospital, Shanghai 200135, P.R. China
| |
Collapse
|
|
39
|
Luz A, Santos M, Magalhães R, Oliveira JC, Pacheco A, Silveira J, Cabral S, Torres S, Leite-Moreira AF, Carvalho H. Soluble TNF-related apoptosis induced ligand (sTRAIL) is augmented by Post-Conditioning and correlates to infarct size and left ventricle dysfunction in STEMI patients: a substudy from a randomized clinical trial. Heart Vessels 2016; 32:117-125. [DOI: 10.1007/s00380-016-0851-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 05/20/2016] [Indexed: 01/15/2023]
|
|
40
|
Xu H, Jin L, Chen Y, Li J. Downregulation of microRNA-429 protects cardiomyocytes against hypoxia-induced apoptosis by increasing Notch1 expression. Int J Mol Med 2016; 37:1677-85. [PMID: 27082497 DOI: 10.3892/ijmm.2016.2558] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 03/17/2016] [Indexed: 11/06/2022] Open
Abstract
Myocardial ischemia is a commonly encountered symptom, chiefly as a result of coronary artery and heart diseases in middle-aged and elderly individuals, with a sudden occurrence and a high morbidity. In some cases, myocardial ischemia may lead to the injury and subsequent death of cardiomyocytes, and may finally culminate in myocardial infarction (MI). MI is the leading cause of sudden death and is associated with a high mortality rate. In this study, we focused on the role of microRNA-429 (miR‑429) in protecting the cardiomyocytes against apoptosis induced by myocardial ischemia. The culture of human cardiomyocytes under hypoxic conditions was employed to mimic myocardial ischemia. miR‑429 expression was upregulated following culture under hypoxic conditions. Subsequently, miR‑429 was artificially overexpressed and silenced by transfection with miRNA-mimics and miRNA-inhibitor, respectively. The results revealed that the downregulation of miR-429 expression exerts protective effects against hypoxia-induced apoptosis. Moreover, Notch1 was also proven to be involved in these protective effects. The downregulation of miR‑429 was accompanied by the activation of Notch1, as indicated by the significant increase in the protein expression of Notch1. The ectopic expression of Notch1 also inhibited the apoptosis induced by culture under hypoxic conditions. In conclusion, and to the best of our knowledge, our results demonstrate for the first time that the downregulation of miR‑429 protects cardiomyocytes against hypoxia-induced apoptosis through Notch1; this may provide the experimental basis for an underlying therapeutic target for myocardial ischemia and consequent MI, as well as the basis for an effective preventive treatment against sudden death.
Collapse
Affiliation(s)
- Han Xu
- Department of Emergency, The Ninth Hospital of Xi'an City, Xi'an, Shaanxi 710054, P.R. China
| | - Long Jin
- The Second Department of Geriatrics, The Ninth Hospital of Xi'an City, Xi'an, Shaanxi 710054, P.R. China
| | - Yan Chen
- Department of Emergency, The Ninth Hospital of Xi'an City, Xi'an, Shaanxi 710054, P.R. China
| | - Junzhi Li
- Department of Emergency, The Ninth Hospital of Xi'an City, Xi'an, Shaanxi 710054, P.R. China
| |
Collapse
|
|
41
|
Baghirova S, Hughes BG, Poirier M, Kondo MY, Schulz R. Nuclear matrix metalloproteinase-2 in the cardiomyocyte and the ischemic-reperfused heart. J Mol Cell Cardiol 2016; 94:153-161. [PMID: 27079252 DOI: 10.1016/j.yjmcc.2016.04.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 04/07/2016] [Indexed: 10/22/2022]
Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent proteases involved in intra- and extra-cellular matrix remodeling resulting from oxidative stress injury to the heart. MMP-2 was the first MMP to be localized to the nucleus; however, its biological functions there are unclear. We hypothesized that MMP-2 is present in the nucleus under normal physiological conditions but increases during myocardial ischemia-reperfusion (I/R) injury-induced oxidative stress, proteolyzing nuclear structural proteins. Lamins are intermediate filament proteins that provide structural support to the nucleus and are putative targets of MMP-2. To identify lamin susceptibility to MMP-2 proteolysis, purified lamin A or B was incubated with MMP-2 in vitro. Lamin A, but not lamin B, was proteolysed by MMP-2 into an approximately 50kDa fragment, which was also predicted by in silico cleavage site analysis. Immunofluorescent confocal microscopy and subcellular fractionation showed MMP-2 both in the cytosol and nuclei of neonatal rat ventricular myocytes. Rat hearts were isolated and perfused by the Langendorff method aerobically, or subjected to I/R injury in the presence or absence of o-phenanthroline, an MMP inhibitor. Nuclear fractions extracted from I/R hearts showed increased MMP-2 activity, but not protein level. The level of troponin I, a known sarcomeric target of MMP-2, was rescued in I/R hearts treated with o-phenanthroline, demonstrating the efficacy of MMP inhibition. However, lamin A or B levels remained unchanged in I/R hearts. MMP-2 has a widespread subcellular distribution in cardiomyocytes, including a significant presence in the nucleus. The increase in nuclear MMP-2 activity seen during stunning injury here, indicates yet unknown biological actions, other than lamin proteolysis, which may require more severe ischemia to effect.
Collapse
Affiliation(s)
- Sabina Baghirova
- Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
| | - Bryan G Hughes
- Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
| | - Mathieu Poirier
- Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
| | - Marcia Y Kondo
- Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
| | - Richard Schulz
- Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
| |
Collapse
|
|
42
|
Jose Corbalan J, Vatner DE, Vatner SF. Myocardial apoptosis in heart disease: does the emperor have clothes? Basic Res Cardiol 2016; 111:31. [PMID: 27043720 DOI: 10.1007/s00395-016-0549-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 03/24/2016] [Indexed: 01/06/2023]
Abstract
Since the discovery of a novel mechanism of cell death that differs from traditional necrosis, i.e., apoptosis, there have been numerous studies concluding that increased apoptosis augments myocardial infarction and heart failure and that limiting apoptosis protects the heart. Importantly, the vast majority of cells in the heart are non-myocytes with only roughly 30 % myocytes, yet almost the entire field studying apoptosis in the heart has disregarded non-myocyte apoptosis, e.g., only 4.7 % of 423 studies on myocardial apoptosis in the past 3 years quantified non-myocyte apoptosis. Accordingly, we reviewed the history of apoptosis in the heart focusing first on myocyte apoptosis, followed by the history of non-myocyte apoptosis in myocardial infarction and heart failure. Apoptosis of several of the major non-myocyte cell types in the heart (cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, macrophages and leukocytes) may actually be responsible for affecting the severity of myocardial infarction and heart failure. In summary, even though it is now known that the majority of apoptosis in the heart occurs in non-myocytes, very little work has been done to elucidate the mechanisms by which non-myocyte apoptosis might be responsible for the adverse effects of apoptosis in myocardial infarction and heart failure. The goal of this review is to provide an impetus for future work in this field on non-myocyte apoptosis that will be required for a better understanding of the role of apoptosis in the heart.
Collapse
Affiliation(s)
- J Jose Corbalan
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, Newark, NJ, 07103, USA
| | - Dorothy E Vatner
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, Newark, NJ, 07103, USA
| | - Stephen F Vatner
- Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, Newark, NJ, 07103, USA.
| |
Collapse
|
|
43
|
Studies on the role of apoptosis after transient myocardial ischemia: genetic deletion of the executioner caspases-3 and -7 does not limit infarct size and ventricular remodeling. Basic Res Cardiol 2016; 111:18. [PMID: 26924441 DOI: 10.1007/s00395-016-0537-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 02/02/2016] [Indexed: 12/13/2022]
Abstract
Although it is widely accepted that apoptosis may contribute to cell death in myocardial infarction, experimental evidence suggests that adult cardiomyocytes repress the expression of the caspase-dependent apoptotic pathway. The aim of this study was to analyze the contribution of caspase-mediated apoptosis to myocardial ischemia-reperfusion injury. Cardiac-specific caspase-3 deficient/full caspase-7-deficient mice (Casp3/7DKO) and wild type control mice (WT) were subjected to in situ ischemia by left anterior coronary artery ligation for 45 min followed by 24 h or 28 days of reperfusion. Heart function was assessed using M-mode echocardiography. Deletion of caspases did not modify neither infarct size determined by triphenyltetrazolium staining after 24 h of reperfusion (40.0 ± 5.1 % in WT vs. 36.2 ± 3.6 % in Casp3/7DKO), nor the scar area measured by pricosirius red staining after 28 days of reperfusion (41.1 ± 5.4 % in WT vs. 44.6 ± 8.7 % in Casp3/7DKO). Morphometric and echocardiographic studies performed 28 days after the ischemic insult revealed left ventricular dilation and severe cardiac dysfunction without statistically significant differences between WT and Casp3/7DKO groups. These data demonstrate that the executioner caspases-3 and -7 do not significantly contribute to cardiomyocyte death induced by transient coronary occlusion and provide the first evidence obtained in an in vivo model that argues against a relevant role of apoptosis through the canonical caspase pathway in this context.
Collapse
|
|
44
|
Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Cardiolipin alterations and mitochondrial dysfunction in heart ischemia/reperfusion injury. ACTA ACUST UNITED AC 2015. [DOI: 10.2217/clp.15.31] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
45
|
Ozyigit F, Kucuk A, Akcer S, Tosun M, Kocak FE, Kocak C, Kocak A, Metineren H, Genc O. Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats. Bosn J Basic Med Sci 2015; 15:36-43. [PMID: 26614850 DOI: 10.17305/bjbms.2015.521] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 06/06/2015] [Accepted: 06/06/2015] [Indexed: 11/16/2022] Open
Abstract
Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R) injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group). Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (p<0.01), levels of MDA, NO, and inducible nitric oxide synthase (iNOS) positive cells (p<0.01, p<0.05, respectively), and increased SOD, GPx, and CAT activities (p<0.001, p<0.01, p<0.05, respectively) compared with the I/R group that did not receive ebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (p<0.01, p<0.05, p<0.001) and MDA and NO levels (p<0.05, p<0.01) and decreased SOD, GPx, and CAT activities (p<0.05) compared with the sham group. The results of this study suggest that ebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects.
Collapse
Affiliation(s)
- Filiz Ozyigit
- Dumlupinar University, Faculty of Medicine, Department of Pharmacology, Kutahya, Turkey.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Wang Y, Zong L, Wang X. TGF-β improves myocardial function and prevents apoptosis induced by anoxia-reoxygenation, through the reduction of endoplasmic reticulum stress. Can J Physiol Pharmacol 2015; 94:9-17. [PMID: 26488543 DOI: 10.1139/cjpp-2014-0466] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Transforming growth factor-β (TGF-β) is known for its role in ventricular remodeling, inflammatory response, cell survival, and apoptosis. However, its role in improving myocardial function in rat hearts subjected to ischemia-reperfusion (I/R) and protecting against apoptosis induced in cardiomyocytes by anoxia-reoxygenation (A/R) has not been elucidated. This study investigated the protective effects and molecular mechanisms of TGF-β on myocardial function and cardiomyocyte apoptosis. METHODS AND RESULTS We used TUNEL staining, we tested cell viability, and we measured mitochondrial membrane potential and levels of mitochondrial ROS after 6 h of simulated anoxia together with various durations of simulated reoxygenation in H9c2 cells. We further observed the contractile function in rat hearts after they were subjected to 30 min global ischemia and 180 min reperfusion. Pretreatment with TGF-β markedly inhibited apoptosis in H9c2 cells, as evidenced by increased cell viability and decreased numbers of TUNEL-positive cells, maintained mitochondrial membrane potential, and diminished mitochondrial production of reactive oxygen species (ROS). These changes were associated with the inhibition of endoplasmic reticulum (ER) stress-dependent markers of apoptosis (GRP78, CHOP, caspase-12, and JNK), and the modulation of the expression of Bcl2/Bax. Furthermore, TGF-β improved I/R-induced myocardial contractile dysfunction. All of these protective effects were concentration-dependent. CONCLUSION Our results show that TGF-β prevents A/R-induced apoptosis of cardiomyocytes and improves myocardial function in rat hearts injured by I/R.
Collapse
Affiliation(s)
- Yufeng Wang
- a Department of Cardiology, Wendeng Central Hospital, Weihai, China
| | - Ligeng Zong
- b Department of Cardiology, Binzhou People's Hospital, Binzhou, China
| | - Xiaolei Wang
- c ICU, Yantai Hospital of Traditional Chinese Medicine, Yantai 264000, China
| |
Collapse
|
|
47
|
Predicting outcome in patients under extracorporeal membrane oxygenation due to cardiogenic shock through dynamic change of lymphocytes and interleukins. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.ijcme.2014.11.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
48
|
Effects of isoflurane postconditioning on chronic phase of ischemia–reperfusion heart injury in rats. Cardiovasc Pathol 2015; 24:94-101. [DOI: 10.1016/j.carpath.2014.09.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 09/09/2014] [Accepted: 09/09/2014] [Indexed: 12/12/2022] Open
|
|
49
|
Chen-Scarabelli C, Agrawal PR, Saravolatz L, Abuniat C, Scarabelli G, Stephanou A, Loomba L, Narula J, Scarabelli TM, Knight R. The role and modulation of autophagy in experimental models of myocardial ischemia-reperfusion injury. J Geriatr Cardiol 2014; 11:338-48. [PMID: 25593583 PMCID: PMC4294150 DOI: 10.11909/j.issn.1671-5411.2014.01.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 10/14/2014] [Accepted: 10/21/2014] [Indexed: 11/21/2022] Open
Abstract
A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cytoplasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion (I/R) injury. This tightly orchestrated catabolic cellular 'housekeeping' process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protective mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the variability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin (mTOR) inhibitors, adenosine monophosphate-activated protein kinase (AMPK) modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic manipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.
Collapse
Affiliation(s)
- Carol Chen-Scarabelli
- VA Ann Arbor Health Care System, University of Michigan, 2215 Fuller Rd, Ann Arbor, MI 48105, USA
| | - Pratik R. Agrawal
- Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, USA
| | - Louis Saravolatz
- St John Hospital and Medical Center, Wayne State University School of Medicine, 22101 Moross Rd., Detroit, MI 48236, USA
| | - Cadigia Abuniat
- St John Hospital and Medical Center, Wayne State University School of Medicine, 22101 Moross Rd., Detroit, MI 48236, USA
| | - Gabriele Scarabelli
- St John Hospital and Medical Center, Wayne State University School of Medicine, 22101 Moross Rd., Detroit, MI 48236, USA
| | - Anastasis Stephanou
- Medical and Molecular Biology Unit, University College London, UCL, 30 Guildford St., London, WC1N 1EH, UK
| | - Leena Loomba
- St John Hospital and Medical Center, Wayne State University School of Medicine, 22101 Moross Rd., Detroit, MI 48236, USA
| | - Jagat Narula
- Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, USA
| | - Tiziano M. Scarabelli
- Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY 10029-6574, USA
- St John Hospital and Medical Center, Wayne State University School of Medicine, 22101 Moross Rd., Detroit, MI 48236, USA
| | - Richard Knight
- Medical and Molecular Biology Unit, University College London, UCL, 30 Guildford St., London, WC1N 1EH, UK
| |
Collapse
|
|
50
|
Huang C, Li J, Hong K, Xia Z, Xu Y, Cheng X. BH3-only protein Bim is upregulated and mediates the apoptosis of cardiomyocytes under glucose and oxygen-deprivation conditions. Cell Biol Int 2014; 39:318-25. [PMID: 25319047 DOI: 10.1002/cbin.10392] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 09/12/2014] [Indexed: 12/31/2022]
Abstract
Bim is a potent pro-apoptotic BH3-only Bcl-2 member. However, the expression of Bim and its role in cardiac injury induced by ischemia remain unclear. H9c2 cells were subjected to a glucose and oxygen-deprived (GOD) condition in vitro, mimicking ischemia environment in vivo. GOD treatment augmented the expression of Bim and induced the apoptosis of H9c2 cells. Silencing of Bim by RNAi significantly attenuated GOD-induced cytotoxicity, suppressed mitochondrial membrane potential △Ψm loss, inhibited caspase 3 activation and reduced apoptosis. The data demonstrate that Bim is upregulated by GOD in a time-dependent manner in H9c2 cells, and enhances mitochondrial apoptosis dependent on the activation of caspase 3. Silencing of Bim may be a promising therapeutic strategy in ischemia related heart diseases.
Collapse
Affiliation(s)
- Chahua Huang
- Department of Cardiology, Second affiliated hospital, Nanchang University, Nanchang, 330006, China
| | | | | | | | | | | |
Collapse
|