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Kumar M, Sengar AS, Lye A, Kumar P, Mukherjee S, Kumar D, Das P, Chatterjee S, Stewart A, Maity B. FNDC5/irisin mitigates the cardiotoxic impacts of cancer chemotherapeutics by modulating ROS-dependent and -independent mechanisms. Redox Biol 2025; 80:103527. [PMID: 39923397 PMCID: PMC11850786 DOI: 10.1016/j.redox.2025.103527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/17/2024] [Accepted: 02/01/2025] [Indexed: 02/11/2025] Open
Abstract
Cardiotoxicity remains a major limiting factor in the clinical implementation of anthracycline chemotherapy. Though the etiology of doxorubicin-dependent heart damage has yet to be fully elucidated, the ability of doxorubicin to damage DNA and trigger oxidative stress have been heavily implicated in the pathogenesis of chemotherapy-associated cardiomyopathy. Here, we demonstrate that fibronectin type III domain-containing protein 5 (FNDC5), the precursor protein for myokine irisin, is depleted in the hearts of human cancer patients or mice exposed to chemotherapeutics. In cardiomyocytes, restoration of FNDC5 expression was sufficient to mitigate reactive oxygen species (ROS) accumulation and apoptosis following doxorubicin exposure, effects dependent on the irisin encoding domain of FNDC5 as well as signaling via the putative irisin integrin receptor. Intriguingly, we identified two parallel signaling cascades impacted by FNDC5 in cardiomyocytes: the ROS-driven intrinsic mitochondrial apoptosis pathway and the ROS-independent Ataxia Telangiectasia and Rad3-Related Protein (ATR)/Checkpoint Kinase 1 (Chk1) pathway. In fact, FNDC5 forms a co-precipitable complex with Chk1 alluding to possible intracellular actions for this canonically membrane-associated protein. Whereas FNDC5 overexpression in murine heart was cardioprotective, introduction of FNDC5-targeted shRNA into the myocardium was sufficient to trigger Bax up-regulation, ATR/Chk1 activation, oxidative stress, cardiac fibrosis, loss of ventricular function, and compromised animal survival. The detrimental impact of FNDC5 depletion on heart function could be mitigated via treatment with a Chk1 inhibitor identifying Chk1 hyperactivity as a causative factor in cardiac disease. Though our data point to the potential clinical utility of FNDC5/irisin-targeted agents in the treatment of chemotherapy-induced cardiotoxicity, we also found significant down regulation in FNDC5 expression in the hearts of aged mice that attenuated the cardioprotective impacts of FNDC5 overexpression following doxorubicin exposure. Together our data underscore the importance of FNDC5/irisin in maintenance of cardiac health over the lifespan.
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Affiliation(s)
- Manish Kumar
- Centre of Biomedical Research, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Abhishek Singh Sengar
- Centre of Biomedical Research, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India
| | - Anushree Lye
- Centre of Biomedical Research, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India; Department of Biological Sciences, Bose Institute, EN 80, Sector V, Kolkata, West Bengal, 700091, India
| | - Pranesh Kumar
- Institute of Pharmaceutical Science, University of Lucknow, Uttar Pradesh, 226007, India
| | - Sukhes Mukherjee
- Department of Biochemistry, AIIMS Bhopal, Saketnagar, Bhopal, Madhya Pradesh, India
| | - Dinesh Kumar
- Centre of Biomedical Research, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India
| | - Priyadip Das
- Department of Chemistry, SRM Institute of Science and Technology, Tamil Nadu, 603203, India
| | - Suvro Chatterjee
- Department of Biotechnology, Burdwan University, West Bengal, 713104, India
| | - Adele Stewart
- Department of Neuroscience & Pharmacology, University of Iowa, Iowa City, IA, 52242, USA
| | - Biswanath Maity
- Centre of Biomedical Research, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India; Department of Biological Sciences, Bose Institute, EN 80, Sector V, Kolkata, West Bengal, 700091, India.
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Wang Z, Zhu H, Xiong W. Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective. Front Med 2025:10.1007/s11684-024-1116-0. [PMID: 39821730 DOI: 10.1007/s11684-024-1116-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 11/04/2024] [Indexed: 01/19/2025]
Abstract
The pursuit of healthy aging has long rendered aging and senescence captivating. Age-related ailments, such as cardiovascular diseases, diabetes, and neurodegenerative disorders, pose significant threats to individuals. Recent studies have shed light on the intricate mechanisms encompassing genetics, epigenetics, transcriptomics, and metabolomics in the processes of senescence and aging, as well as the establishment of age-related pathologies. Amidst these underlying mechanisms governing aging and related pathology metabolism assumes a pivotal role that holds promise for intervention and therapeutics. The advancements in metabolomics techniques and analysis methods have significantly propelled the study of senescence and aging, particularly with the aid of multiscale metabolomics which has facilitated the discovery of metabolic markers and therapeutic potentials. This review provides an overview of senescence and aging, emphasizing the crucial role metabolism plays in the aging process as well as age-related diseases.
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Affiliation(s)
- Ziyi Wang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Hongying Zhu
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230088, China.
- CAS Key Laboratory of Brain Function and Disease, Hefei, 230026, China.
- Anhui Province Key Laboratory of Biomedical Aging Research, Hefei, 230026, China.
| | - Wei Xiong
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
- Anhui Province Key Laboratory of Biomedical Imaging and Intelligent Processing, Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230088, China.
- CAS Key Laboratory of Brain Function and Disease, Hefei, 230026, China.
- Anhui Province Key Laboratory of Biomedical Aging Research, Hefei, 230026, China.
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3
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Zhao H, Cao N, Liu Q, Zhang Y, Jin R, Lai H, Zheng L, Zhang H, Zhu Y, Ma Y, Yang Z, Wu Z, Li W, Liu Y, Cheng L, Chen Y. Inhibition of the E3 ligase UBR5 stabilizes TERT and protects vascular organoids from oxidative stress. J Transl Med 2024; 22:1080. [PMID: 39609696 PMCID: PMC11605888 DOI: 10.1186/s12967-024-05887-0] [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: 09/01/2024] [Accepted: 11/14/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND Excessive oxidative stress is known to cause endothelial dysfunction and drive cardiovascular diseases (CVD). While telomerase reverse transcriptase (TERT) shows protective effects against oxidative stress in rodents and is associated to human flow-mediated dilation in CVD, its regulatory mechanisms in human vascular systems under pathological oxidative stress require further investigation. METHODS Human induced pluripotent stem cells (hiPSCs) were used to create vascular organoids (VOs). These VOs and human umbilical vein endothelial cells (HUVECs) were subjected to oxidative stress through both hydrogen peroxide (H2O2) and oxidized low-density lipoprotein (oxLDL) models. The effects of TERT overexpression by inhibition of the ubiquitin protein ligase E3 component N-recognin 5 (UBR5) on reactive oxygen species (ROS)-induced vascular injury and cellular senescence were assessed using neovascular sprouting assays, senescence-associated β-galactosidase (SA-β-Gal) staining, and senescence-associated secretory phenotype (SASP) assays. RESULTS ROS significantly impaired VO development and endothelial progenitor cell (EPC) angiogenesis, evidenced by reduced neovascular sprouting and increased senescence markers, including elevated SA-β-Gal activity and SASP-related cytokine levels. Overexpression of TERT counteracted these effects, restoring VO development and EPC function. Immunoprecipitation-mass spectrometry identified UBR5 as a critical TERT regulator, facilitating its degradation. Inhibition of UBR5 stabilized TERT, improving VO angiogenic capacity, and reducing SA-β-Gal activity and SASP cytokine levels. CONCLUSIONS Inhibiting UBR5 stabilizes TERT, which preserves EPC angiogenic capacity, reduces VO impairment, and delays endothelial cell senescence under oxidative stress. These findings highlight the potential of targeting UBR5 to enhance vascular health in oxidative stress-related conditions.
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Affiliation(s)
- Haijing Zhao
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Nian Cao
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China
| | - Qi Liu
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Yingyue Zhang
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Rui Jin
- Beijing Institute of Biotechnology, Beijing, 100850, People's Republic of China
| | - Huiying Lai
- Department of Clinical Laboratory, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China
| | - Li Zheng
- School of Medicine, Nankai University, Tianjin, 300071, People's Republic of China
| | - Honghong Zhang
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Yue Zhu
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Yuhan Ma
- School of Medicine, Nankai University, Tianjin, 300071, People's Republic of China
| | - Zengao Yang
- School of Medicine, South China University of Technology, Guangzhou, 510006, People's Republic of China
| | - Zhengfeng Wu
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China
- Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China
| | - Weini Li
- Department of Biomedical Science, Cedars-Sinai Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA
| | - Yuqi Liu
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China.
- National Key Laboratory of Kidney Diseases, Beijing, 100853, People's Republic of China.
- Department of Cardiology, National Clinical Research Center of Geriatric Disease, Beijing, 100853, People's Republic of China.
- Beijing Key Laboratory of Chronic Heart Failure Precision Medicine, Beijing, 100853, People's Republic of China.
| | - Long Cheng
- The Key Laboratory of Geriatrics, Institute of Geriatric Medicine, Beijing Institute of Geriatrics, Chinese Academy of Medical Sciences, Beijing Hospital/National Centre of Gerontology of National Health Commission, Beijing, 100730, People's Republic of China.
- Beijing Institute of Biotechnology, Beijing, 100850, People's Republic of China.
| | - Yundai Chen
- Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, 100037, People's Republic of China.
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Prajapat SK, Maharana KC, Singh S. Mitochondrial dysfunction in the pathogenesis of endothelial dysfunction. Mol Cell Biochem 2024; 479:1999-2016. [PMID: 37642880 DOI: 10.1007/s11010-023-04835-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/14/2023] [Indexed: 08/31/2023]
Abstract
Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction.
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Affiliation(s)
- Suresh Kumar Prajapat
- National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, Hajipur, Bihar, India
| | - Krushna Ch Maharana
- National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, Hajipur, Bihar, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP), Industrial Area, Dist: Vaishali, Hajipur, Bihar, 844102, India.
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Ma S, Xie X, Yuan R, Xin Q, Miao Y, Leng SX, Chen K, Cong W. Vascular Aging and Atherosclerosis: A Perspective on Aging. Aging Dis 2024; 16:AD.2024.0201-1. [PMID: 38502584 PMCID: PMC11745439 DOI: 10.14336/ad.2024.0201-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/01/2024] [Indexed: 03/21/2024] Open
Abstract
Vascular aging (VA) is recognized as a pivotal factor in the development and progression of atherosclerosis (AS). Although various epidemiological and clinical research has demonstrated an intimate connection between aging and AS, the candidate mechanisms still require thorough examination. This review adopts an aging-centric perspective to deepen the comprehension of the intricate relationship between biological aging, vascular cell senescence, and AS. Various aging-related physiological factors influence the physical system's reactions, including oxygen radicals, inflammation, lipids, angiotensin II, mechanical forces, glucose levels, and insulin resistance. These factors cause endothelial dysfunction, barrier damage, sclerosis, and inflammation for VA and promote AS via distinct or shared pathways. Furthermore, the increase of senescent cells inside the vascular tissues, caused by genetic damage, dysregulation, secretome changes, and epigenetic modifications, might be the primary cause of VA.
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Affiliation(s)
- Shudong Ma
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xuena Xie
- School of Pharmacy, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Rong Yuan
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Qiqi Xin
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Yu Miao
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Sean Xiao Leng
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
| | - Keji Chen
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Weihong Cong
- School of Pharmacy, Macau University of Science and Technology, Macau, China.
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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6
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Nie X, Fan J, Dai B, Wen Z, Li H, Chen C, Wang DW. LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2. Circ Res 2024; 134:425-441. [PMID: 38299365 DOI: 10.1161/circresaha.123.323428] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 01/18/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined. METHODS Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription-polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA-fluorescence in situ hybridization, and Western blotting. RESULTS CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction-induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and fused in sarcoma (FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-HNE (4-hydroxy-2-nonenal) production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT+/- mice alleviated cardiac dilation and dysfunction. CONCLUSIONS CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.
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MESH Headings
- Animals
- Humans
- Mice
- Adenosine Triphosphate/metabolism
- Aldehyde Dehydrogenase, Mitochondrial/genetics
- Aldehyde Dehydrogenase, Mitochondrial/metabolism
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/metabolism
- Down-Regulation
- In Situ Hybridization, Fluorescence
- Mice, Knockout
- Mitochondria, Heart/metabolism
- Myocytes, Cardiac/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
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Affiliation(s)
- Xiang Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College (X.N., J.F., B.D., Z.W., H.L., C.C., D.W.W.), Huazhong University of Science and Technology, Wuhan, China
| | - Jiahui Fan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College (X.N., J.F., B.D., Z.W., H.L., C.C., D.W.W.), Huazhong University of Science and Technology, Wuhan, China
| | - Beibei Dai
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College (X.N., J.F., B.D., Z.W., H.L., C.C., D.W.W.), Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders (B.D., Z.W., H.L.), Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Wen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College (X.N., J.F., B.D., Z.W., H.L., C.C., D.W.W.), Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders (B.D., Z.W., H.L.), Huazhong University of Science and Technology, Wuhan, China
| | - Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College (X.N., J.F., B.D., Z.W., H.L., C.C., D.W.W.), Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders (B.D., Z.W., H.L.), Huazhong University of Science and Technology, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College (X.N., J.F., B.D., Z.W., H.L., C.C., D.W.W.), Huazhong University of Science and Technology, Wuhan, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College (X.N., J.F., B.D., Z.W., H.L., C.C., D.W.W.), Huazhong University of Science and Technology, Wuhan, China
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7
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Caminiti R, Carresi C, Mollace R, Macrì R, Scarano F, Oppedisano F, Maiuolo J, Serra M, Ruga S, Nucera S, Tavernese A, Gliozzi M, Musolino V, Palma E, Muscoli C, Rubattu S, Volterrani M, Federici M, Volpe M, Mollace V. The potential effect of natural antioxidants on endothelial dysfunction associated with arterial hypertension. Front Cardiovasc Med 2024; 11:1345218. [PMID: 38370153 PMCID: PMC10869541 DOI: 10.3389/fcvm.2024.1345218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 01/15/2024] [Indexed: 02/20/2024] Open
Abstract
Arterial hypertension represents a leading cause of cardiovascular morbidity and mortality worldwide, and the identification of effective solutions for treating the early stages of elevated blood pressure (BP) is still a relevant issue for cardiovascular risk prevention. The pathophysiological basis for the occurrence of elevated BP and the onset of arterial hypertension have been widely studied in recent years. In addition, consistent progress in the development of novel, powerful, antihypertensive drugs and their appropriate applications in controlling BP have increased our potential for successfully managing disease states characterized by abnormal blood pressure. However, the mechanisms responsible for the disruption of endogenous mechanisms contributing to the maintenance of BP within a normal range are yet to be fully clarified. Recently, evidence has shown that several natural antioxidants containing active ingredients originating from natural plant extracts, used alone or in combination, may represent a valid solution for counteracting the development of arterial hypertension. In particular, there is evidence to show that natural antioxidants may enhance the viability of endothelial cells undergoing oxidative damage, an effect that could play a crucial role in the pathophysiological events accompanying the early stages of arterial hypertension. The present review aims to reassess the role of oxidative stress on endothelial dysfunction in the onset and progression of arterial hypertension and that of natural antioxidants in covering several unmet needs in the treatment of such diseases.
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Affiliation(s)
- Rosamaria Caminiti
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Cristina Carresi
- Department of Health Sciences, Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Rocco Mollace
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
- Department of Systems Medicine, University “Tor Vergata” of Rome, Rome, Italy
| | - Roberta Macrì
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Federica Scarano
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Francesca Oppedisano
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Jessica Maiuolo
- Laboratory of Pharmaceutical Biology, Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Maria Serra
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Stefano Ruga
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Saverio Nucera
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Annamaria Tavernese
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Micaela Gliozzi
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Vincenzo Musolino
- Laboratory of Pharmaceutical Biology, Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Ernesto Palma
- Department of Health Sciences, Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
| | - Carolina Muscoli
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
- IRCCS San Raffaele Roma, Rome, Italy
| | - Speranza Rubattu
- IRCCS Neuromed, Pozzilli, Italy
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University, Rome, Italy
| | | | - Massimo Federici
- Department of Systems Medicine, University “Tor Vergata” of Rome, Rome, Italy
| | | | - Vincenzo Mollace
- Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Graecia” of Catanzaro, Catanzaro, Italy
- Renato Dulbecco Institute, Catanzaro, Italy
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8
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Pandics T, Major D, Fazekas-Pongor V, Szarvas Z, Peterfi A, Mukli P, Gulej R, Ungvari A, Fekete M, Tompa A, Tarantini S, Yabluchanskiy A, Conley S, Csiszar A, Tabak AG, Benyo Z, Adany R, Ungvari Z. Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures. GeroScience 2023; 45:3381-3408. [PMID: 37688657 PMCID: PMC10643494 DOI: 10.1007/s11357-023-00913-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/14/2023] [Indexed: 09/11/2023] Open
Abstract
The aging population worldwide is facing a significant increase in age-related non-communicable diseases, including cardiovascular and brain pathologies. This comprehensive review paper delves into the impact of the exposome, which encompasses the totality of environmental exposures, on unhealthy aging. It explores how environmental factors contribute to the acceleration of aging processes, increase biological age, and facilitate the development and progression of a wide range of age-associated diseases. The impact of environmental factors on cognitive health and the development of chronic age-related diseases affecting the cardiovascular system and central nervous system is discussed, with a specific focus on Alzheimer's disease, Parkinson's disease, stroke, small vessel disease, and vascular cognitive impairment (VCI). Aging is a major risk factor for these diseases. Their pathogenesis involves cellular and molecular mechanisms of aging such as increased oxidative stress, impaired mitochondrial function, DNA damage, and inflammation and is influenced by environmental factors. Environmental toxicants, including ambient particulate matter, pesticides, heavy metals, and organic solvents, have been identified as significant contributors to cardiovascular and brain aging disorders. These toxicants can inflict both macro- and microvascular damage and many of them can also cross the blood-brain barrier, inducing neurotoxic effects, neuroinflammation, and neuronal dysfunction. In conclusion, environmental factors play a critical role in modulating cardiovascular and brain aging. A deeper understanding of how environmental toxicants exacerbate aging processes and contribute to the pathogenesis of neurodegenerative diseases, VCI, and dementia is crucial for the development of preventive strategies and interventions to promote cardiovascular, cerebrovascular, and brain health. By mitigating exposure to harmful environmental factors and promoting healthy aging, we can strive to reduce the burden of age-related cardiovascular and brain pathologies in the aging population.
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Affiliation(s)
- Tamas Pandics
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- Department of Public Health Laboratory, National Public Health Centre, Budapest, Hungary
- Department of Public Health Siences, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary
| | - David Major
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Vince Fazekas-Pongor
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Zsofia Szarvas
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anna Peterfi
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Peter Mukli
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Rafal Gulej
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anna Ungvari
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Monika Fekete
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Anna Tompa
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Stefano Tarantini
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Andriy Yabluchanskiy
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Shannon Conley
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Adam G Tabak
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- UCL Brain Sciences, University College London, London, UK
- Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Zoltan Benyo
- Department of Translational Medicine, Semmelweis University, Budapest, Hungary
- Eötvös Loránd Research Network and Semmelweis University (ELKH-SE) Cerebrovascular and Neurocognitive Disorders Research Group, Budapest, H-1052, Hungary
| | - Roza Adany
- Department of Public Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- ELKH-DE Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
- Epidemiology and Surveillance Centre, Semmelweis University, 1085, Budapest, Hungary
| | - Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA.
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
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9
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Liu S, He Y, Zhang Y, Zhang Z, Huang K, Deng L, Liao B, Zhong Y, Feng J. Targeting gut microbiota in aging-related cardiovascular dysfunction: focus on the mechanisms. Gut Microbes 2023; 15:2290331. [PMID: 38073096 PMCID: PMC10730151 DOI: 10.1080/19490976.2023.2290331] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
The global population is aging and age-related cardiovascular disease is increasing. Even after controlling for cardiovascular risk factors, readmission and mortality rates remain high. In recent years, more and more in-depth studies have found that the composition of the gut microbiota and its metabolites, such as trimethylamine N-oxide (TMAO), bile acids (BAs), and short-chain fatty acids (SCFAs), affect the occurrence and development of age-related cardiovascular diseases through a variety of molecular pathways, providing a new target for therapy. In this review, we discuss the relationship between the gut microbiota and age-related cardiovascular diseases, and propose that the gut microbiota could be a new therapeutic target for preventing and treating cardiovascular diseases.
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Affiliation(s)
- Siqi Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Yufeng He
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Yali Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Zhaolun Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Keming Huang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Li Deng
- Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Yi Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
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10
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Heusch G, Andreadou I, Bell R, Bertero E, Botker HE, Davidson SM, Downey J, Eaton P, Ferdinandy P, Gersh BJ, Giacca M, Hausenloy DJ, Ibanez B, Krieg T, Maack C, Schulz R, Sellke F, Shah AM, Thiele H, Yellon DM, Di Lisa F. Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection. Redox Biol 2023; 67:102894. [PMID: 37839355 PMCID: PMC10590874 DOI: 10.1016/j.redox.2023.102894] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/04/2023] [Accepted: 09/15/2023] [Indexed: 10/17/2023] Open
Abstract
The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal.
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Affiliation(s)
- Gerd Heusch
- Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany.
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Robert Bell
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Edoardo Bertero
- Chair of Cardiovascular Disease, Department of Internal Medicine and Specialties, University of Genova, Genova, Italy
| | - Hans-Erik Botker
- Department of Cardiology, Institute for Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - James Downey
- Department of Physiology, University of South Alabama, Mobile, AL, USA
| | - Philip Eaton
- William Harvey Research Institute, Queen Mary University of London, Heart Centre, Charterhouse Square, London, United Kingdom
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary
| | - Bernard J Gersh
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Mauro Giacca
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College, London, United Kingdom
| | - Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom; Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, National Heart Research Institute Singapore, National Heart Centre, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), IIS-Fundación Jiménez Díaz University Hospital, and CIBERCV, Madrid, Spain
| | - Thomas Krieg
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Christoph Maack
- Department of Translational Research, Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
| | - Rainer Schulz
- Institute for Physiology, Justus-Liebig -Universität, Giessen, Germany
| | - Frank Sellke
- Division of Cardiothoracic Surgery, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI, USA
| | - Ajay M Shah
- King's College London British Heart Foundation Centre of Excellence, London, United Kingdom
| | - Holger Thiele
- Heart Center Leipzig at University of Leipzig and Leipzig Heart Science, Leipzig, Germany
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, London, United Kingdom
| | - Fabio Di Lisa
- Dipartimento di Scienze Biomediche, Università degli studi di Padova, Padova, Italy.
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11
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Kuntic M, Kuntic I, Hahad O, Lelieveld J, Münzel T, Daiber A. Impact of air pollution on cardiovascular aging. Mech Ageing Dev 2023; 214:111857. [PMID: 37611809 DOI: 10.1016/j.mad.2023.111857] [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: 07/06/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023]
Abstract
The world population is aging rapidly, and by some estimates, the number of people older than 60 will double in the next 30 years. With the increase in life expectancy, adverse effects of environmental exposures start playing a more prominent role in human health. Air pollution is now widely considered the most detrimental of all environmental risk factors, with some studies estimating that almost 20% of all deaths globally could be attributed to poor air quality. Cardiovascular diseases are the leading cause of death worldwide and will continue to account for the most significant percentage of non-communicable disease burden. Cardiovascular aging with defined pathomechanisms is a major trigger of cardiovascular disease in old age. Effects of environmental risk factors on cardiovascular aging should be considered in order to increase the health span and reduce the burden of cardiovascular disease in older populations. In this review, we explore the effects of air pollution on cardiovascular aging, from the molecular mechanisms to cardiovascular manifestations of aging and, finally, the age-related cardiovascular outcomes. We also explore the distinction between the effects of air pollution on healthy aging and disease progression. Future efforts should focus on extending the health span rather than the lifespan.
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Affiliation(s)
- Marin Kuntic
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany
| | - Ivana Kuntic
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany
| | - Omar Hahad
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany
| | - Jos Lelieveld
- Max Planck Institute for Chemistry, Atmospheric Chemistry, Mainz, Germany
| | - Thomas Münzel
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.
| | - Andreas Daiber
- University Medical Center Mainz, Department for Cardiology 1, Molecular Cardiology, Mainz, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, Germany.
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12
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Abstract
ABSTRACT The incidence of abdominal aortic aneurysm (AAA) in the elderly is increasing year by year with high mortality. Current treatment is mainly through surgery or endovascular intervention, which is not sufficient to reduce future risk. Therefore, we still need to find an effective conservative measure as an adjunct therapy or early intervention to prevent AAA progression. Traditional therapeutic agents, such as β-receptor blockers, calcium channel blockers, and statins, have been shown to have limited effects on the growth of AAA. Recently, sodium-glucose cotransport proteins inhibitors (SGLT2is), a new class hypoglycemic drug, have shown outstanding beneficiary effects on cardiovascular diseases by plasma volume reduction, vascular tone regulation, and various unidentified mechanisms. It has been demonstrated that SGLT2i is abundantly expressed in the aorta, and some studies also showed promising results of SGLT2i in treating animal AAA models. This article aims to summarize the recent progress of AAA studies and look forward to the application of SGLT2i in AAA treatment for early intervention or adjunct therapy after surgical repair or stent graft.
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Affiliation(s)
- Zhongtiao Jin
- Master of Medicine, Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China; and
| | - Hongping Deng
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, 430060, China.
| | - Sizheng Xiong
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, 430060, China.
| | - Ling Gao
- Master of Medicine, Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China; and
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13
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Li YJ, Jin X, Li D, Lu J, Zhang XN, Yang SJ, Zhao YX, Wu M. New insights into vascular aging: Emerging role of mitochondria function. Biomed Pharmacother 2022; 156:113954. [DOI: 10.1016/j.biopha.2022.113954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022] Open
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14
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Strohm L, Ubbens H, Münzel T, Daiber A, Daub S. Role of CD40(L)-TRAF signaling in inflammation and resolution-a double-edged sword. Front Pharmacol 2022; 13:995061. [PMID: 36267276 PMCID: PMC9577411 DOI: 10.3389/fphar.2022.995061] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/12/2022] [Indexed: 11/26/2022] Open
Abstract
Cardiovascular diseases (CVD) and cardiovascular risk factors are the leading cause of death in the world today. According to the Global Burden of Disease Study, hypertension together with ischemic heart and cerebrovascular diseases is responsible for approximately 40% of all deaths worldwide. The major pathomechanism underlying almost all CVD is atherosclerosis, an inflammatory disorder of the vascular system. Recent large-scale clinical trials demonstrated that inflammation itself is an independent cardiovascular risk factor. Specific anti-inflammatory therapy could decrease cardiovascular mortality in patients with atherosclerosis (increased markers of inflammation). Inflammation, however, can also be beneficial by conferring so-called resolution, a process that contributes to clearing damaged tissue from cell debris upon cell death and thereby represents an essential step for recovery from, e.g., ischemia/reperfusion damage. Based on these considerations, the present review highlights features of the detrimental inflammatory reactions as well as of the beneficial process of immune cell-triggered resolution. In this context, we discuss the polarization of macrophages to either M1 or M2 phenotype and critically assess the role of the CD40L-CD40-TRAF signaling cascade in atherosclerosis and its potential link to resolution. As CD40L can bind to different cellular receptors, it can initiate a broad range of inflammatory processes that may be detrimental or beneficial. Likewise, the signaling of CD40L downstream of CD40 is mainly determined by activation of TRAF1-6 pathways that again can be detrimental or beneficial. Accordingly, CD40(L)-based therapies may be Janus-faced and require sophisticated fine-tuning in order to promote cardioprotection.
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Affiliation(s)
- Lea Strohm
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Henning Ubbens
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Steffen Daub
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
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15
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Clayton ZS, Craighead DH, Darvish S, Coppock M, Ludwig KR, Brunt VE, Seals DR, Rossman MJ. Promoting healthy cardiovascular aging: emerging topics. THE JOURNAL OF CARDIOVASCULAR AGING 2022; 2:43. [PMID: 36337728 PMCID: PMC9632540 DOI: 10.20517/jca.2022.27] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The development of age-related cardiovascular (CV) dysfunction increases the risk of CV disease as well as other chronic age-associated disorders, including chronic kidney disease, and Alzheimer's disease and related dementias. Major manifestations of age-associated CV dysfunction that increase disease risk are vascular dysfunction, primarily vascular endothelial dysfunction and arterial stiffening, and elevated systolic blood pressure. Declines in nitric oxide bioavailability secondary to increased oxidative stress and inflammation are established mechanisms of CV dysfunction with aging. Moreover, fundamental mechanisms of aging, termed the "hallmarks of aging" extend to the CV system and, as such, may be considered "hallmarks of CV aging". These mechanisms represent viable therapeutic targets for treating CV dysfunction with aging. Healthy lifestyle behaviors, such as regular aerobic exercise and certain dietary patterns, are considered "first-line" strategies to prevent and/or treat age-associated CV dysfunction. Despite the well-established benefits of these strategies, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related CV dysfunction. Targeting fundamental mechanisms of CV aging with interventions such as time-efficient exercise training, food-derived molecules, termed nutraceuticals, or select synthetic pharmacological agents represents a promising approach. In the present review, we will highlight emerging topics in the field of healthy CV aging with a specific focus on how exercise, nutrition/dietary patterns, nutraceuticals and select synthetic pharmacological compounds may promote healthy CV aging, in part, by targeting the hallmarks of CV aging.
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Affiliation(s)
- Zachary S Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Daniel H Craighead
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Sanna Darvish
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - McKinley Coppock
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Katelyn R Ludwig
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Vienna E Brunt
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Matthew J Rossman
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
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16
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Sung JY, Kim SG, Kang YJ, Choi HC. Metformin mitigates stress-induced premature senescence by upregulating AMPKα at Ser485 phosphorylation induced SIRT3 expression and inactivating mitochondrial oxidants. Mech Ageing Dev 2022; 206:111708. [PMID: 35863470 DOI: 10.1016/j.mad.2022.111708] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 01/10/2023]
Abstract
The senescence of vascular smooth muscle cells (VSMCs) is an important cause of cardiovascular disease such as atherosclerosis and hypertension. These senescence may be triggered by many factors, such as oxidative stress, inflammation, DNA damage, and senescence-associated secretory phenotypes (SASPs). Mitochondrial oxidative stress induces cellular senescence, but the mechanisms by which mitochondrial reactive oxygen species (mtROS) regulates cellular senescence are still largely unknown. Here, we investigated the mechanism responsible for the anti-aging effect of metformin by examining links between VSMC senescence and mtROS in in vitro and in vivo. Metformin was found to increase p-AMPK (Ser485), but to decrease senescence-associated phenotypes and protein levels of senescence markers during ADR-induced VSMC senescence. Importantly, metformin decreased mtROS by inducing the deacetylation of superoxide dismutase 2 (SOD2) by increasing SIRT3 expression. Moreover, AMPK depletion reduced the expression of SIRT3 and increased the expression of acetylated SOD2 despite metformin treatment, suggesting AMPK activation by metformin is required to protect against mitochondrial oxidative stress by SIRT3. This study provides mechanistic evidence that metformin acts as an anti-aging agent and alleviates VSMC senescence by upregulating mitochondrial antioxidant induced p-AMPK (Ser485)-dependent SIRT3 expression, which suggests metformin has therapeutic potential for the treatment of age-associated vascular disease.
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Affiliation(s)
- Jin Young Sung
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Seul Gi Kim
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Young Jin Kang
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Hyoung Chul Choi
- Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, Republic of Korea; Smart-aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
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17
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Baszyński J, Kamiński P, Bogdzińska M, Mroczkowski S, Szymański M, Wasilow K, Stanek E, Hołderna-Bona K, Brodzka S, Bilski R, Tkachenko H, Kurhaluk N, Stuczyński T, Lorek M, Woźniak A. Enzymatic Antioxidant Defense and Polymorphic Changes in Male Infertility. Antioxidants (Basel) 2022; 11:817. [PMID: 35624681 PMCID: PMC9138092 DOI: 10.3390/antiox11050817] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/15/2022] [Accepted: 04/16/2022] [Indexed: 01/27/2023] Open
Abstract
The intensification of oxidative stress and destabilization of the antioxidative defenses of an organism is a consequence of many environmental factors. We considered aspects conditioning male reproductive potential and the functionality of enzymatic antioxidative mechanisms, i.e., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), and their correlations with Li, Be, B, Na, Mg, Al, P, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Ag, Cd, Sn, Sb, Ba, Hg, Tl, Pb, and malondialdehyde (MDA), as well as genetic polymorphism IL-4v.C589T (rs2243250) in men with infertility (n = 76). A healthy normozoospermic control (n = 87) was also used. We assessed the impact of negative changes driven by oxidative stress on enzymatic antioxidative mechanisms as well as the role of MDA in the overall process. On this basis, we infer connections between disturbances in enzymatic antioxidative defense and reproductive potential. Based on a molecular analysis of the polymorphism of gene IL-4v.C589T (rs2243250) (chromosome 5) (PCR-RFLP), we considered the relationships among particular genotypes with the possibility of occurrence of male infertility. Concentrations of chemical elements were measured in the blood. The activity of antioxidants and MDA levels were measured in serum. In the infertile group, higher GPx activity was noted (6.56 nmoL·min-1·mL-1, control: 4.31 nmoL·min-1·mL-1; p = 0.004), while GR achieved a greater level in the control (17.74 nmoL·min-1·mL-1, infertile: 15.97 nmoL·min-1·mL-1, p = 0.043), which implies diversified efficiency of the first and second lines of defense. The polymorphism of IL-4v.C589T (rs2243250) was not directly connected with infertility because there were not any differences in the frequency of genotypes between the infertile and control group (p = 0.578). An analysis of genotypes CC and TT (polymorphism IL-4v.C589T (rs2243250)) indicated numerous correlations between antioxidants, chemical elements and MDA. Therefore, chemical economy, antioxidative defense and genetic conditions are connected and jointly shape male reproductive potential. Chemical elements influence antioxidative defense and male fertility; the most important modulators appeared to be Na, Ba, Al and B. The polymorphism of gene IL-4v.C589T (rs2243250) has a limited influence on antioxidative defense and the metabolism of chemical elements.
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Affiliation(s)
- Jędrzej Baszyński
- Department of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (J.B.); (E.S.); (K.H.-B.); (S.B.); (M.L.)
| | - Piotr Kamiński
- Department of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (J.B.); (E.S.); (K.H.-B.); (S.B.); (M.L.)
- Department of Biotechnology, Faculty of Biological Sciences, Institute of Biological Sciences, University of Zielona Góra, Prof. Z. Szafran St. 1, PL 65-516 Zielona Góra, Poland
| | - Maria Bogdzińska
- Department of Genetics and Animal Breeding, Faculty of Animal Breeding and Biology, UTP University of Science and Technology in Bydgoszcz, Hetmańska St. 33, PL 85-039 Bydgoszcz, Poland; (M.B.); (S.M.)
| | - Sławomir Mroczkowski
- Department of Genetics and Animal Breeding, Faculty of Animal Breeding and Biology, UTP University of Science and Technology in Bydgoszcz, Hetmańska St. 33, PL 85-039 Bydgoszcz, Poland; (M.B.); (S.M.)
| | - Marek Szymański
- Department of Obstetrics, Female Pathology and Oncological Gynecology, University Hospital No. 2, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Ujejski St. 75, PL 85-168 Bydgoszcz, Poland;
- NZOZ Medical Center Co., Waleniowa St. 24, PL 85-435 Bydgoszcz, Poland;
| | - Karolina Wasilow
- NZOZ Medical Center Co., Waleniowa St. 24, PL 85-435 Bydgoszcz, Poland;
- Family Medicine Clinic, University Hospital No. 2, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Ujejski St. 75, PL 85-168 Bydgoszcz, Poland
| | - Emilia Stanek
- Department of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (J.B.); (E.S.); (K.H.-B.); (S.B.); (M.L.)
| | - Karolina Hołderna-Bona
- Department of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (J.B.); (E.S.); (K.H.-B.); (S.B.); (M.L.)
| | - Sylwia Brodzka
- Department of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (J.B.); (E.S.); (K.H.-B.); (S.B.); (M.L.)
| | - Rafał Bilski
- Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Karłowicz St. 24, PL 85-092 Bydgoszcz, Poland; (R.B.); or (A.W.)
| | - Halyna Tkachenko
- Department of Biology, Institute of Biology and Earth Sciences, Pomeranian University in Słupsk, K. Arciszewski St. 22 B, PL 76-200 Słupsk, Poland; (H.T.); (N.K.)
| | - Natalia Kurhaluk
- Department of Biology, Institute of Biology and Earth Sciences, Pomeranian University in Słupsk, K. Arciszewski St. 22 B, PL 76-200 Słupsk, Poland; (H.T.); (N.K.)
| | - Tomasz Stuczyński
- Department of Soil Structure, Institute of Soil and Plant Cultivation-Government Scientific Institute, Czartoryskich St. 8, PL 24-100 Puławy, Poland; or
- Faculty of Mathematics Informatics and Landscape Architecture, The John Paul II Catholic University of Lublin, Konstantynów 1 H, PL 20-708 Lublin, Poland
| | - Małgorzata Lorek
- Department of Ecology and Environmental Protection, Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Skłodowska-Curie St. 9, PL 85-094 Bydgoszcz, Poland; (J.B.); (E.S.); (K.H.-B.); (S.B.); (M.L.)
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, M. Karłowicz St. 24, PL 85-092 Bydgoszcz, Poland; (R.B.); or (A.W.)
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18
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Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM, Sinclair DA. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol 2022; 18:243-258. [PMID: 35145250 PMCID: PMC9059418 DOI: 10.1038/s41574-021-00626-7] [Citation(s) in RCA: 425] [Impact Index Per Article: 141.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/17/2021] [Indexed: 12/11/2022]
Abstract
Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches.
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Affiliation(s)
- João A Amorim
- Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA
- Center for Neurosciences and Cell Biology of the University of Coimbra, Coimbra, Portugal
- IIIUC, Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Giuseppe Coppotelli
- Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA
- George and Anne Ryan Institute for Neuroscience, College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA
| | - Anabela P Rolo
- Center for Neurosciences and Cell Biology of the University of Coimbra, Coimbra, Portugal
- Department of Life Sciences of the University of Coimbra, Coimbra, Portugal
| | - Carlos M Palmeira
- Center for Neurosciences and Cell Biology of the University of Coimbra, Coimbra, Portugal
- Department of Life Sciences of the University of Coimbra, Coimbra, Portugal
| | - Jaime M Ross
- Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA
- George and Anne Ryan Institute for Neuroscience, College of Pharmacy, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA
| | - David A Sinclair
- Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA.
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19
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Trinity JD, Drummond MJ, Fermoyle CC, McKenzie AI, Supiano MA, Richardson RS. Cardiovasomobility: an integrative understanding of how disuse impacts cardiovascular and skeletal muscle health. J Appl Physiol (1985) 2022; 132:835-861. [PMID: 35112929 PMCID: PMC8934676 DOI: 10.1152/japplphysiol.00607.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Cardiovasomobility is a novel concept that encompasses the integration of cardiovascular and skeletal muscle function in health and disease with critical modification by physical activity, or lack thereof. Compelling evidence indicates that physical activity improves health while a sedentary, or inactive, lifestyle accelerates cardiovascular and skeletal muscle dysfunction and hastens disease progression. Identifying causative factors for vascular and skeletal muscle dysfunction, especially in humans, has proven difficult due to the limitations associated with cross-sectional investigations. Therefore, experimental models of physical inactivity and disuse, which mimic hospitalization, injury, and illness, provide important insight into the mechanisms and consequences of vascular and skeletal muscle dysfunction. This review provides an overview of the experimental models of disuse and inactivity and focuses on the integrated responses of the vasculature and skeletal muscle in response to disuse/inactivity. The time course and magnitude of dysfunction evoked by various models of disuse/inactivity are discussed in detail, and evidence in support of the critical roles of mitochondrial function and oxidative stress are presented. Lastly, strategies aimed at preserving vascular and skeletal muscle dysfunction during disuse/inactivity are reviewed. Within the context of cardiovasomobility, experimental manipulation of physical activity provides valuable insight into the mechanisms responsible for vascular and skeletal muscle dysfunction that limit mobility, degrade quality of life, and hasten the onset of disease.
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Affiliation(s)
- Joel D Trinity
- Salt Lake City Veteran Affairs Medical Center Geriatric Research, Education, and Clinical Center, Salt Lake City, Utah.,Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah.,Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
| | - Micah J Drummond
- Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah.,Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah.,Department of Physical Therapy, University of Utah, Salt Lake City, Utah
| | - Caitlin C Fermoyle
- Salt Lake City Veteran Affairs Medical Center Geriatric Research, Education, and Clinical Center, Salt Lake City, Utah.,Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah
| | - Alec I McKenzie
- Salt Lake City Veteran Affairs Medical Center Geriatric Research, Education, and Clinical Center, Salt Lake City, Utah.,Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah
| | - Mark A Supiano
- Salt Lake City Veteran Affairs Medical Center Geriatric Research, Education, and Clinical Center, Salt Lake City, Utah.,Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah
| | - Russell S Richardson
- Salt Lake City Veteran Affairs Medical Center Geriatric Research, Education, and Clinical Center, Salt Lake City, Utah.,Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, Utah.,Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah
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20
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Tran N, Garcia T, Aniqa M, Ali S, Ally A, Nauli SM. Endothelial Nitric Oxide Synthase (eNOS) and the Cardiovascular System: in Physiology and in Disease States. AMERICAN JOURNAL OF BIOMEDICAL SCIENCE & RESEARCH 2022; 15:153-177. [PMID: 35072089 PMCID: PMC8774925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Endothelial nitric oxide synthase (eNOS) plays a critical role in regulating and maintaining a healthy cardiovascular system. The importance of eNOS can be emphasized from the genetic polymorphisms of the eNOS gene, uncoupling of eNOS dimerization, and its numerous signaling regulations. The activity of eNOS on the cardiac myocytes, vasculature, and the central nervous system are discussed. The effects of eNOS on the sympathetic autonomic nervous system (SANS) and the parasympathetic autonomic nervous system (PANS), both of which profoundly influence the cardiovascular system, will be elaborated. The relationship between the eNOS protein with cardiovascular autonomic reflexes such as the baroreflex and the Exercise Pressor Reflex will be discussed. For example, the effects of endogenous nitric oxide (NO) are shown to be mediated by the eNOS protein and that eNOS-derived endothelial NO is most effective in regulating blood pressure oscillations via modulating the baroreflex mechanisms. The protective action of eNOS on the CVS is emphasized here because dysfunction of the eNOS enzyme is intricately correlated with the pathogenesis of several cardiovascular diseases such as hypertension, arteriosclerosis, myocardial infarction, and stroke. Overall, our current understanding of the eNOS protein with a focus on its role in the modulation, regulation, and control of the cardiovascular system in a normal physiological state and in cardiovascular diseases are discussed.
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Affiliation(s)
- N Tran
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, USA
| | - T Garcia
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, USA
| | - M Aniqa
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, USA
| | - S Ali
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, USA
| | - A Ally
- Arkansas College of Osteopathic Medicine, Fort Smith, AR, USA,Corresponding author: Surya M Nauli, Chapman University and University of California, Irvine, CA, USA
| | - SM Nauli
- Chapman University and University of California, Irvine, CA, USA,Corresponding author: Surya M Nauli, Chapman University and University of California, Irvine, CA, USA
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21
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The effects of real and simulated microgravity on cellular mitochondrial function. NPJ Microgravity 2021; 7:44. [PMID: 34750383 PMCID: PMC8575887 DOI: 10.1038/s41526-021-00171-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 10/07/2021] [Indexed: 11/22/2022] Open
Abstract
Astronauts returning from space shuttle missions or the International Space Station have been diagnosed with various health problems such as bone demineralization, muscle atrophy, cardiovascular deconditioning, and vestibular and sensory imbalance including visual acuity, altered metabolic and nutritional status, and immune system dysregulation. These health issues are associated with oxidative stress caused by a microgravity environment. Mitochondria are a source of reactive oxygen species (ROS). However, the molecular mechanisms through which mitochondria produce ROS in a microgravity environment remain unclear. Therefore, this review aimed to explore the mechanism through which microgravity induces oxidative damage in mitochondria by evaluating the expression of genes and proteins, as well as relevant metabolic pathways. In general, microgravity-induced ROS reduce mitochondrial volume by mainly affecting the efficiency of the respiratory chain and metabolic pathways. The impaired respiratory chain is thought to generate ROS through premature electron leakage in the electron transport chain. The imbalance between ROS production and antioxidant defense in mitochondria is the main cause of mitochondrial stress and damage, which leads to mitochondrial dysfunction. Moreover, we discuss the effects of antioxidants against oxidative stress caused by the microgravity environment space microgravity in together with simulated microgravity (i.e., spaceflight or ground-based spaceflight analogs: parabolic flight, centrifugal force, drop towers, etc.). Further studies should be taken to explore the effects of microgravity on mitochondrial stress-related diseases, especially for the development of new therapeutic drugs that can help increase the health of astronauts on long space missions.
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22
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Tracy EP, Hughes W, Beare JE, Rowe G, Beyer A, LeBlanc AJ. Aging-Induced Impairment of Vascular Function: Mitochondrial Redox Contributions and Physiological/Clinical Implications. Antioxid Redox Signal 2021; 35:974-1015. [PMID: 34314229 PMCID: PMC8905248 DOI: 10.1089/ars.2021.0031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: The vasculature responds to the respiratory needs of tissue by modulating luminal diameter through smooth muscle constriction or relaxation. Coronary perfusion, diastolic function, and coronary flow reserve are drastically reduced with aging. This loss of blood flow contributes to and exacerbates pathological processes such as angina pectoris, atherosclerosis, and coronary artery and microvascular disease. Recent Advances: Increased attention has recently been given to defining mechanisms behind aging-mediated loss of vascular function and development of therapeutic strategies to restore youthful vascular responsiveness. The ultimate goal aims at providing new avenues for symptom management, reversal of tissue damage, and preventing or delaying of aging-induced vascular damage and dysfunction in the first place. Critical Issues: Our major objective is to describe how aging-associated mitochondrial dysfunction contributes to endothelial and smooth muscle dysfunction via dysregulated reactive oxygen species production, the clinical impact of this phenomenon, and to discuss emerging therapeutic strategies. Pathological changes in regulation of mitochondrial oxidative and nitrosative balance (Section 1) and mitochondrial dynamics of fission/fusion (Section 2) have widespread effects on the mechanisms underlying the ability of the vasculature to relax, leading to hyperconstriction with aging. We will focus on flow-mediated dilation, endothelial hyperpolarizing factors (Sections 3 and 4), and adrenergic receptors (Section 5), as outlined in Figure 1. The clinical implications of these changes on major adverse cardiac events and mortality are described (Section 6). Future Directions: We discuss antioxidative therapeutic strategies currently in development to restore mitochondrial redox homeostasis and subsequently vascular function and evaluate their potential clinical impact (Section 7). Antioxid. Redox Signal. 35, 974-1015.
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Affiliation(s)
- Evan Paul Tracy
- Department of Physiology, University of Louisville, Louisville, Kentucky, USA
| | - William Hughes
- Department of Medicine and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jason E Beare
- Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA.,Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, USA
| | - Gabrielle Rowe
- Department of Physiology, University of Louisville, Louisville, Kentucky, USA
| | - Andreas Beyer
- Department of Medicine and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Amanda Jo LeBlanc
- Department of Physiology, University of Louisville, Louisville, Kentucky, USA.,Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky, USA
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23
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Aramide Modupe Dosunmu-Ogunbi A, Galley JC, Yuan S, Schmidt HM, Wood KC, Straub AC. Redox Switches Controlling Nitric Oxide Signaling in the Resistance Vasculature and Implications for Blood Pressure Regulation: Mid-Career Award for Research Excellence 2020. Hypertension 2021; 78:912-926. [PMID: 34420371 DOI: 10.1161/hypertensionaha.121.16493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The arterial resistance vasculature modulates blood pressure and flow to match oxygen delivery to tissue metabolic demand. As such, resistance arteries and arterioles have evolved a series of highly orchestrated cell-cell communication mechanisms between endothelial cells and vascular smooth muscle cells to regulate vascular tone. In response to neurohormonal agonists, release of several intracellular molecules, including nitric oxide, evokes changes in vascular tone. We and others have uncovered novel redox switches in the walls of resistance arteries that govern nitric oxide compartmentalization and diffusion. In this review, we discuss our current understanding of redox switches controlling nitric oxide signaling in endothelial and vascular smooth muscle cells, focusing on new mechanistic insights, physiological and pathophysiological implications, and advances in therapeutic strategies for hypertension and other diseases.
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Affiliation(s)
- Atinuke Aramide Modupe Dosunmu-Ogunbi
- Heart, Lung, Blood and Vascular Medicine Institute (A.A.M.D.-O., J.C.G., S.Y., H.M.S., K.C.W., A.C.S.), University of Pittsburgh, PA.,Department of Pharmacology and Chemical Biology (A.A.M.D.-O., J.C.G., H.M.S., A.C.S), University of Pittsburgh, PA
| | - Joseph C Galley
- Heart, Lung, Blood and Vascular Medicine Institute (A.A.M.D.-O., J.C.G., S.Y., H.M.S., K.C.W., A.C.S.), University of Pittsburgh, PA.,Department of Pharmacology and Chemical Biology (A.A.M.D.-O., J.C.G., H.M.S., A.C.S), University of Pittsburgh, PA
| | - Shuai Yuan
- Heart, Lung, Blood and Vascular Medicine Institute (A.A.M.D.-O., J.C.G., S.Y., H.M.S., K.C.W., A.C.S.), University of Pittsburgh, PA
| | - Heidi M Schmidt
- Heart, Lung, Blood and Vascular Medicine Institute (A.A.M.D.-O., J.C.G., S.Y., H.M.S., K.C.W., A.C.S.), University of Pittsburgh, PA.,Department of Pharmacology and Chemical Biology (A.A.M.D.-O., J.C.G., H.M.S., A.C.S), University of Pittsburgh, PA
| | - Katherine C Wood
- Heart, Lung, Blood and Vascular Medicine Institute (A.A.M.D.-O., J.C.G., S.Y., H.M.S., K.C.W., A.C.S.), University of Pittsburgh, PA
| | - Adam C Straub
- Heart, Lung, Blood and Vascular Medicine Institute (A.A.M.D.-O., J.C.G., S.Y., H.M.S., K.C.W., A.C.S.), University of Pittsburgh, PA.,Department of Pharmacology and Chemical Biology (A.A.M.D.-O., J.C.G., H.M.S., A.C.S), University of Pittsburgh, PA.,Center for Microvascular Research (A.C.S.), University of Pittsburgh, PA
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24
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Ding YN, Wang HY, Chen HZ, Liu DP. Targeting senescent cells for vascular aging and related diseases. J Mol Cell Cardiol 2021; 162:43-52. [PMID: 34437878 DOI: 10.1016/j.yjmcc.2021.08.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/08/2021] [Accepted: 08/17/2021] [Indexed: 01/10/2023]
Abstract
Cardiovascular diseases are a serious threat to human health, especially in the elderly. Vascular aging makes people more susceptible to cardiovascular diseases due to significant dysfunction or senescence of vascular cells and maladaptation of vascular structure and function; moreover, vascular aging is currently viewed as a modifiable cardiovascular risk factor. To emphasize the relationship between senescent cells and vascular aging, we first summarize the roles of senescent vascular cells (endothelial cells, smooth muscle cells and immune cells) in the vascular aging process and inducers that contribute to cellular senescence. Then, we present potential strategies for directly targeting senescent cells (senotherapy) or preventively targeting senescence inducers (senoprevention) to delay vascular aging and the development of age-related vascular diseases. Finally, based on recent research, we note some important questions that still need to be addressed in the future.
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Affiliation(s)
- Yang-Nan Ding
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, People's Republic of China
| | - Hui-Yu Wang
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, People's Republic of China
| | - Hou-Zao Chen
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, People's Republic of China.
| | - De-Pei Liu
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, People's Republic of China.
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25
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Birk M, Baum E, Zadeh JK, Manicam C, Pfeiffer N, Patzak A, Helmstädter J, Steven S, Kuntic M, Daiber A, Gericke A. Angiotensin II Induces Oxidative Stress and Endothelial Dysfunction in Mouse Ophthalmic Arteries via Involvement of AT1 Receptors and NOX2. Antioxidants (Basel) 2021; 10:antiox10081238. [PMID: 34439486 PMCID: PMC8389243 DOI: 10.3390/antiox10081238] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 12/13/2022] Open
Abstract
Angiotensin II (Ang II) has been implicated in the pathophysiology of various age-dependent ocular diseases. The purpose of this study was to test the hypothesis that Ang II induces endothelial dysfunction in mouse ophthalmic arteries and to identify the underlying mechanisms. Ophthalmic arteries were exposed to Ang II in vivo and in vitro to determine vascular function by video microscopy. Moreover, the formation of reactive oxygen species (ROS) was quantified and the expression of prooxidant redox genes and proteins was determined. The endothelium-dependent artery responses were blunted after both in vivo and in vitro exposure to Ang II. The Ang II type 1 receptor (AT1R) blocker, candesartan, and the ROS scavenger, Tiron, prevented Ang II-induced endothelial dysfunction. ROS levels and NOX2 expression were increased following Ang II incubation. Remarkably, Ang II failed to induce endothelial dysfunction in ophthalmic arteries from NOX2-deficient mice. Following Ang II incubation, endothelium-dependent vasodilation was mainly mediated by cytochrome P450 oxygenase (CYP450) metabolites, while the contribution of nitric oxide synthase (NOS) and 12/15-lipoxygenase (12/15-LOX) pathways became negligible. These findings provide evidence that Ang II induces endothelial dysfunction in mouse ophthalmic arteries via AT1R activation and NOX2-dependent ROS formation. From a clinical point of view, the blockade of AT1R signaling and/or NOX2 may be helpful to retain or restore endothelial function in ocular blood vessels in certain ocular diseases.
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Affiliation(s)
- Michael Birk
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.B.); (E.B.); (J.K.Z.); (C.M.); (N.P.)
- Department of Ophthalmology, University Eye Hospital Tübingen, Elfriede-Aulhorn-Straße 7, 72076 Tübingen, Germany
| | - Ewa Baum
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.B.); (E.B.); (J.K.Z.); (C.M.); (N.P.)
- Department of Social Sciences and the Humanities, Poznan University of Medical Sciences, ul. Rokietnicka 7, 60-806 Poznań, Poland
| | - Jenia Kouchek Zadeh
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.B.); (E.B.); (J.K.Z.); (C.M.); (N.P.)
| | - Caroline Manicam
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.B.); (E.B.); (J.K.Z.); (C.M.); (N.P.)
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.B.); (E.B.); (J.K.Z.); (C.M.); (N.P.)
| | - Andreas Patzak
- Institute of Vegetative Physiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany;
| | - Johanna Helmstädter
- Department of Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center, Johannes Gutenberg University, Building 605, Langenbeckstr. 1, 55131 Mainz, Germany; (J.H.); (S.S.); (M.K.); (A.D.)
| | - Sebastian Steven
- Department of Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center, Johannes Gutenberg University, Building 605, Langenbeckstr. 1, 55131 Mainz, Germany; (J.H.); (S.S.); (M.K.); (A.D.)
| | - Marin Kuntic
- Department of Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center, Johannes Gutenberg University, Building 605, Langenbeckstr. 1, 55131 Mainz, Germany; (J.H.); (S.S.); (M.K.); (A.D.)
| | - Andreas Daiber
- Department of Cardiology, Cardiology I-Laboratory of Molecular Cardiology, University Medical Center, Johannes Gutenberg University, Building 605, Langenbeckstr. 1, 55131 Mainz, Germany; (J.H.); (S.S.); (M.K.); (A.D.)
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.B.); (E.B.); (J.K.Z.); (C.M.); (N.P.)
- Correspondence: ; Tel.: +49-613-117-8276
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Hartwick Bjorkman S, Oliveira Pereira R. The Interplay Between Mitochondrial Reactive Oxygen Species, Endoplasmic Reticulum Stress, and Nrf2 Signaling in Cardiometabolic Health. Antioxid Redox Signal 2021; 35:252-269. [PMID: 33599550 PMCID: PMC8262388 DOI: 10.1089/ars.2020.8220] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Mitochondria-derived reactive oxygen species (mtROS) are by-products of normal physiology that may disrupt cellular redox homeostasis on a regular basis. Nonetheless, failure to resolve sustained mitochondrial stress to mitigate high levels of mtROS might contribute to the etiology of numerous pathological conditions, such as obesity, insulin resistance, and cardiovascular disease (CVD). Recent Advances: Notably, recent studies have demonstrated that moderate mitochondrial stress might result in the induction of different stress response pathways that ultimately improve the organism's ability to deal with subsequent stress, a process termed mitohormesis. mtROS have been shown to play a key role in regulating this adaptation. Critical Issue: mtROS regulate the convergence of different signaling pathways that, when disturbed, might impair cardiometabolic health. Conversely, mtROS seem to be required to mediate activation of prosurvival pathways, contributing to improved cardiometabolic fitness. In the present review, we will primarily focus on the role of mtROS in the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway and examine the role of endoplasmic reticulum (ER) stress in coordinating the convergence of ER stress and oxidative stress signaling through activation of Nrf2 and activating transcription factor 4 (ATF4). Future Directions: The mechanisms underlying cardiometabolic protection in response to mitochondrial stress have only started to be investigated. Integrated understanding of how mtROS and ER stress cooperatively promote activation of prosurvival pathways might shed mechanistic insight into the role of mitohormesis in mediating cardiometabolic protection and might inform future therapeutic avenues for the treatment of metabolic diseases contributing to CVD. Antioxid. Redox Signal. 35, 252-269.
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Affiliation(s)
- Sarah Hartwick Bjorkman
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.,Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | - Renata Oliveira Pereira
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
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Hahad O, Frenis K, Kuntic M, Daiber A, Münzel T. Accelerated Aging and Age-Related Diseases (CVD and Neurological) Due to Air Pollution and Traffic Noise Exposure. Int J Mol Sci 2021; 22:2419. [PMID: 33670865 PMCID: PMC7957813 DOI: 10.3390/ijms22052419] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/23/2021] [Accepted: 02/23/2021] [Indexed: 12/13/2022] Open
Abstract
The World Health Organization estimates that only approximately 25% of diversity in longevity is explained by genetic factors, while the other 75% is largely determined by interactions with the physical and social environments. Indeed, aging is a multifactorial process that is influenced by a range of environmental, sociodemographic, and biopsychosocial factors, all of which might act in concert to determine the process of aging. The global average life expectancy increased fundamentally over the past century, toward an aging population, correlating with the development and onset of age-related diseases, mainly from cardiovascular and neurological nature. Therefore, the identification of determinants of healthy and unhealthy aging is a major goal to lower the burden and socioeconomic costs of age-related diseases. The role of environmental factors (such as air pollution and noise exposure) as crucial determinants of the aging process are being increasingly recognized. Here, we critically review recent findings concerning the pathomechanisms underlying the aging process and their correlates in cardiovascular and neurological disease, centered on oxidative stress and inflammation, as well as the influence of prominent environmental pollutants, namely air pollution and traffic noise exposure, which is suggested to accelerate the aging process. Insight into these types of relationships and appropriate preventive strategies are urgently needed to promote healthy aging.
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Affiliation(s)
- Omar Hahad
- Department of Cardiology, University Medical Center Mainz, Johannes Gutenberg University, 55131 Mainz, Germany; (O.H.); (K.F.); (M.K.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
| | - Katie Frenis
- Department of Cardiology, University Medical Center Mainz, Johannes Gutenberg University, 55131 Mainz, Germany; (O.H.); (K.F.); (M.K.)
| | - Marin Kuntic
- Department of Cardiology, University Medical Center Mainz, Johannes Gutenberg University, 55131 Mainz, Germany; (O.H.); (K.F.); (M.K.)
| | - Andreas Daiber
- Department of Cardiology, University Medical Center Mainz, Johannes Gutenberg University, 55131 Mainz, Germany; (O.H.); (K.F.); (M.K.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, University Medical Center Mainz, Johannes Gutenberg University, 55131 Mainz, Germany; (O.H.); (K.F.); (M.K.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
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28
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Li X, Lu L, Chen J, Zhang C, Chen H, Huang H. New Insight into the Mechanisms of Ginkgo Biloba Extract in Vascular Aging Prevention. Curr Vasc Pharmacol 2020; 18:334-345. [PMID: 31223090 DOI: 10.2174/1570161117666190621150725] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 05/07/2019] [Accepted: 05/14/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Aging-associated vascular dysfunction promotes cardiovascular diseases. Recently, Ginkgo biloba extract (GBE) has attracted considerable attention in the prevention of aged vasculature. METHODS This review discusses the pathophysiological alterations in aged vasculature and the underlying mechanisms of GBE in vascular aging suppression. RESULTS Both arterial stiffening and endothelial dysfunction are critical aging-related vascular phenotypes that result in the progression of cardiovascular diseases in the general population. Consistent oxidative stress and inflammatory reaction lead to vascular dysfunction. GBE ameliorates aging-related vascular dysfunction, due to its antioxidant and anti-inflammatory properties. The main effects of GBE in aged vasculature might be associated with the longevity signaling pathways. GBE also attenuates the progression of vascular aging in diabetes mellitus via regulation of glucose and lipid metabolism. CONCLUSION GBE plays an important role in the prevention of vascular aging process. It is a promising therapeutic approach to ameliorate aging-related vascular dysfunction and cardiovascular diseases.
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Affiliation(s)
- Xiaoxue Li
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Liuyi Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jie Chen
- Department of Radiation Oncology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chao Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hong Chen
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States
| | - Hui Huang
- Department of Cardiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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29
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Clayton ZS, Brunt VE, Hutton DA, VanDongen NS, D’Alessandro A, Reisz JA, Ziemba BP, Seals DR. Doxorubicin-Induced Oxidative Stress and Endothelial Dysfunction in Conduit Arteries Is Prevented by Mitochondrial-Specific Antioxidant Treatment. JACC: CARDIOONCOLOGY 2020; 2:475-488. [PMID: 33073250 PMCID: PMC7561020 DOI: 10.1016/j.jaccao.2020.06.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Doxorubicin (DOXO) chemotherapy increases risk for cardiovascular disease in part by inducing endothelial dysfunction in conduit arteries. However, the mechanisms mediating DOXO-associated endothelial dysfunction in (intact) arteries and treatment strategies are not established. Objectives We tested the hypothesis that DOXO impairs endothelial function in conduit arteries via excessive mitochondrial reactive oxygen species (ROS) and that these effects could be prevented by treatment with a mitochondrial-targeted antioxidant (MitoQ). Methods Endothelial function (endothelium-dependent dilation [EDD] to acetylcholine) and vascular mitochondrial ROS were assessed 4 weeks following administration (10 mg/kg intraperitoneal injection) of DOXO. A separate cohort of mice received chronic (4 weeks) oral supplementation with MitoQ (drinking water) for 4 weeks following DOXO. Results EDD in isolated pressurized carotid arteries was 55% lower 4 weeks following DOXO (peak EDD, DOXO: 42 ± 7% vs. sham: 94 ± 3%; p = 0.006). Vascular mitochondrial ROS was 52% higher and manganese (mitochondrial) superoxide dismutase was 70% lower after DOXO versus sham (p = 0.0008). Endothelial function was rescued by administration of the mitochondrial-targeted antioxidant, MitoQ, to the perfusate. Exposure to plasma from DOXO-treated mice increased mitochondrial ROS in cultured endothelial cells. Analyses of plasma showed differences in oxidative stress-related metabolites and a marked reduction in vascular endothelial growth factor A in DOXO mice, and restoring vascular endothelial growth factor A to sham levels normalized mitochondrial ROS in endothelial cells incubated with plasma from DOXO mice. Oral MitoQ supplementation following DOXO prevented the reduction in EDD (97 ± 1%; p = 0.002 vs. DOXO alone) by ameliorating mitochondrial ROS suppression of EDD. Conclusions DOXO-induced endothelial dysfunction in conduit arteries is mediated by excessive mitochondrial ROS and ameliorated by mitochondrial-specific antioxidant treatment. Mitochondrial ROS is a viable therapeutic target for mitigating arterial dysfunction with DOXO.
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Affiliation(s)
- Zachary S. Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Vienna E. Brunt
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - David A. Hutton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Nicholas S. VanDongen
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Angelo D’Alessandro
- Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA
| | - Julie A. Reisz
- Department of Medicine, Anschutz Medical Campus, University of Colorado Denver, Aurora, Colorado, USA
| | - Brian P. Ziemba
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Douglas R. Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
- Address for correspondence: Dr. Douglas R. Seals, Department of Integrative Physiology, University of Colorado Boulder, 1725 Pleasant Street, 354 UCB, Boulder, Colorado 80309.
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30
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Decoding the role of SOD2 in sickle cell disease. Blood Adv 2020; 3:2679-2687. [PMID: 31506286 DOI: 10.1182/bloodadvances.2019000527] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 07/23/2019] [Indexed: 12/11/2022] Open
Abstract
Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a single point mutation in the β-globin gene. As a consequence, deoxygenated hemoglobin polymerizes triggering red blood cell sickling and hemolysis, vaso-occlusion, and ischemia/reperfusion. Allied to these pathologies is the overproduction of reactive oxygen species driven by hemoglobin Fenton chemistry and peroxidase reactions as well as by secondary activation of vascular oxidases, including NAD(P)H oxidase and xanthine oxidase. In addition, hypoxia, produced by sickle red blood cell occlusion, disrupts mitochondrial metabolism and generates excess superoxide through electron leak from the mitochondrial respiratory chain. Superoxide dismutase 2 (SOD2) is a mitochondrial-specific antioxidant enzyme that dismutates superoxide to hydrogen peroxide, which is then converted to water by catalase and glutathione peroxidase. In SCD, the antioxidant defense system is significantly diminished through decreased expression and activity levels of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. From a translational perspective, genetic variants including a missense variant in SOD2 (valine to alanine at position 16) are present in 45% of people with African ancestry and are associated with increased sickle complications. While it is known that there is an imbalance between oxidative species and antioxidant defenses in SCD, much more investigation is warranted. This review summarizes our current understanding of antioxidant defense systems in SCD, particularly focused on SOD2, and provides insight into challenges and opportunities as the field moves forward.
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Daiber A, Chlopicki S. Revisiting pharmacology of oxidative stress and endothelial dysfunction in cardiovascular disease: Evidence for redox-based therapies. Free Radic Biol Med 2020; 157:15-37. [PMID: 32131026 DOI: 10.1016/j.freeradbiomed.2020.02.026] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/05/2020] [Accepted: 02/26/2020] [Indexed: 02/07/2023]
Abstract
According to the latest Global Burden of Disease Study data, non-communicable diseases in general and cardiovascular disease (CVD) in particular are the leading cause of premature death and reduced quality of life. Demographic shifts, unhealthy lifestyles and a higher burden of adverse environmental factors provide an explanation for these findings. The expected growing prevalence of CVD requires enhanced research efforts for identification and characterisation of novel therapeutic targets and strategies. Cardiovascular risk factors including classical (e.g. hypertension, diabetes, hypercholesterolaemia) and non-classical (e.g. environmental stress) factors induce the development of endothelial dysfunction, which is closely associated with oxidant stress and vascular inflammation and results in CVD, particularly in older adults. Most classically successful therapies for CVD display vasoprotective, antioxidant and anti-inflammatory effects, but were originally designed with other therapeutic aims. So far, only a few 'redox drugs' are in clinical use and many antioxidant strategies have not met expectations. With the present review, we summarise the actual knowledge on CVD pathomechanisms, with special emphasis on endothelial dysfunction, adverse redox signalling and oxidative stress, highlighting the preclinical and clinical evidence. In addition, we provide a brief overview of established CVD therapies and their relation to endothelial dysfunction and oxidative stress. Finally, we discuss novel strategies for redox-based CVD therapies trying to explain why, despite a clear link between endothelial dysfunction and adverse redox signalling and oxidative stress, redox- and oxidative stress-based therapies have not yet provided a breakthrough in the treatment of endothelial dysfunction and CVD.
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Affiliation(s)
- Andreas Daiber
- The Center for Cardiology, Department of Cardiology 1, Laboratory of Molecular Cardiology, University Medical Center, Langenbeckstr. 1, 55131, Mainz, Germany; The Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Langenbeckstr. 1, 55131, Mainz, Germany.
| | - Stefan Chlopicki
- The Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348, Krakow, Poland; Jagiellonian University Medical College, Grzegorzecka 16, 31-531, Krakow, Poland.
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32
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Yang J, Suo H, Song J. Protective role of mitoquinone against impaired mitochondrial homeostasis in metabolic syndrome. Crit Rev Food Sci Nutr 2020; 61:3857-3875. [PMID: 32815398 DOI: 10.1080/10408398.2020.1809344] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mitochondria control various processes in cellular metabolic homeostasis, such as adenosine triphosphate production, generation and clearance of reactive oxygen species, control of intracellular Ca2+ and apoptosis, and are thus a critical therapeutic target for metabolic syndrome (MetS). The mitochondrial targeted antioxidant mitoquinone (MitoQ) reduces mitochondrial oxidative stress, prevents impaired mitochondrial dynamics, and increases mitochondrial turnover by promoting autophagy (mitophagy) and mitochondrial biogenesis, which ultimately contribute to the attenuation of MetS conditions, including obesity, insulin resistance, hypertension and cardiovascular disease. The regulatory effect of MitoQ on mitochondrial homeostasis is mediated through AMPK and its downstream signaling pathways, including MTOR, SIRT1, Nrf2 and NF-κB. However, there are few reviews focusing on the critical role of MitoQ as a therapeutic agent in the treatment of MetS. The purpose of this review is to summarize the mitochondrial role in the pathogenesis of MetS, especially in obesity and type 2 diabetes, and discuss the effect and underlying mechanism of MitoQ on mitochondrial homeostasis in MetS.
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Affiliation(s)
- Jing Yang
- Chongqing Engineering Research Center for Processing & Storage of Distinct Agricultural Products, Chongqing Technology and Business University, Chongqing, China.,Graduate School, Chongqing Technology and Business University, Chongqing, China
| | - Huayi Suo
- College of Food Science, Southwest University, Chongqing, China
| | - Jiajia Song
- College of Food Science, Southwest University, Chongqing, China
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Hussain S, Khan AW, Akhmedov A, Suades R, Costantino S, Paneni F, Caidahl K, Mohammed SA, Hage C, Gkolfos C, Björck H, Pernow J, Lund LH, Lüscher TF, Cosentino F. Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD. Circ Res 2020; 127:1261-1273. [PMID: 32815777 DOI: 10.1161/circresaha.120.317132] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
RATIONALE Hyperglycemia -induced reactive oxygen species are key mediators of cardiac dysfunction. JunD (Jund proto-oncogene subunit), a member of the AP-1 (activator protein-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to redox state and inflammation in the diabetic heart remains to be elucidated. OBJECTIVE The present study investigates the role of JunD in hyperglycemia-induced and reactive oxygen species-driven myocardial dysfunction. METHODS AND RESULTS JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes mellitus as compared to controls. JunD downregulation was associated with oxidative stress and left ventricular dysfunction assessed by electron spin resonance spectroscopy as well as conventional and 2-dimensional speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the NOX2 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 2) and NOX4 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 4) were upregulated. The redox changes were associated with increased NF-κB (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the α MHC (α- myosin heavy chain) promoter (α MHC JunDtg) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, post-translational modification of histone marks, and translational repression by miRNA (microRNA)-673/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes mellitus as compared to nondiabetic subjects. CONCLUSIONS Here, we show that a complex epigenetic machinery involving DNA methylation, histone modifications, and microRNAs mediates hyperglycemia-induced JunD downregulation and myocardial dysfunction in experimental and human diabetes mellitus. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.
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Affiliation(s)
- Shafaat Hussain
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
| | - Abdul Waheed Khan
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
| | - Alexander Akhmedov
- Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)
| | - Rosa Suades
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
| | - Sarah Costantino
- Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.).,University Heart Center and Department of Research and Education, University Hospital Zürich, Switzerland (F.P.)
| | - Kenneth Caidahl
- Department of Molecular Medicine and Surgery (K.C.), Karolinska Institutet, Stockholm, Sweden.,Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden (K.C.)
| | - Shafeeq A Mohammed
- Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)
| | - Camilla Hage
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
| | - Christos Gkolfos
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
| | - Hanna Björck
- Center for Molecular Medicine, Department of Medicine (H.B.), Karolinska Institutet, Stockholm, Sweden
| | - John Pernow
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
| | - Lars H Lund
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)
| | - Francesco Cosentino
- Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)
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Targeting mitochondrial fitness as a strategy for healthy vascular aging. Clin Sci (Lond) 2020; 134:1491-1519. [PMID: 32584404 DOI: 10.1042/cs20190559] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/01/2020] [Accepted: 06/03/2020] [Indexed: 02/06/2023]
Abstract
Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations ('research gaps') for future investigation.
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35
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Forte M, Stanzione R, Cotugno M, Bianchi F, Marchitti S, Rubattu S. Vascular ageing in hypertension: Focus on mitochondria. Mech Ageing Dev 2020; 189:111267. [PMID: 32473170 DOI: 10.1016/j.mad.2020.111267] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 12/25/2022]
Abstract
Hypertension is a common age-related disease, along with vascular and neurodegenerative diseases. Vascular ageing increases during hypertension, but hypertension itself accelerates vascular ageing, thus creating a vicious circle. Vascular stiffening, endothelial dysfunction, impaired contractility and vasorelaxation are the main alterations related to vascular ageing, as a consequence of vascular smooth muscle and endothelial cells senescence. Several molecular mechanisms have been involved into the functional and morphological changes of the aged vessels. Among them, oxidative stress, inflammation, extracellular matrix deregulation and mitochondrial dysfunction are the best characterized. In the present review, we discuss relevant literature about the biology of vascular and cerebrovascular ageing with a particular focus on mitochondria signalling. We underline the therapeutic strategies, able to improve mitochondrial health, which may represent a promising tool to decrease vascular dysfunction associated with ageing and hypertension-related complications.
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Affiliation(s)
- Maurizio Forte
- IRCCS Neuromed, Via Atinense, 18, 86077 Pozzilli IS, Italy
| | | | - Maria Cotugno
- IRCCS Neuromed, Via Atinense, 18, 86077 Pozzilli IS, Italy
| | - Franca Bianchi
- IRCCS Neuromed, Via Atinense, 18, 86077 Pozzilli IS, Italy
| | | | - Speranza Rubattu
- IRCCS Neuromed, Via Atinense, 18, 86077 Pozzilli IS, Italy; Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy.
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Regulation of Vascular Function and Inflammation via Cross Talk of Reactive Oxygen and Nitrogen Species from Mitochondria or NADPH Oxidase-Implications for Diabetes Progression. Int J Mol Sci 2020; 21:ijms21103405. [PMID: 32408480 PMCID: PMC7279344 DOI: 10.3390/ijms21103405] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-mediated damage. Here, the pathways and potential mechanisms leading to this cross talk are analyzed in detail and highlighted by selected examples from the current literature and own data including hypoxia, angiotensin II (AT-II)-induced hypertension, nitrate tolerance, aging, and others. The general concept of redox-based activation of RONS sources via “kindling radicals” and enzyme-specific “redox switches” as well as the interaction with redox-sensitive inflammatory pathways are discussed. Here, we present evidence for the existence of such cross talk mechanisms in the setting of diabetes and critically assess their contribution to the severity of diabetic complications.
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Abstract
Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.
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Affiliation(s)
- Zoltan Ungvari
- From the Vascular Cognitive Impairment Laboratory, Reynolds Oklahoma Center on Aging (Z.U., S.T., A.C.), University of Oklahoma Health Sciences Center, Oklahoma City
- Department of Geriatric Medicine, Translational Geroscience Laboratory (Z.U., S.T., A.C.), University of Oklahoma Health Sciences Center, Oklahoma City
- Department of Medical Physics and Informatics, University of Szeged, Hungary (Z.U., A.C.)
- Department of Pulmonology, Semmelweis University of Medicine, Budapest, Hungary (Z.U.)
| | - Stefano Tarantini
- From the Vascular Cognitive Impairment Laboratory, Reynolds Oklahoma Center on Aging (Z.U., S.T., A.C.), University of Oklahoma Health Sciences Center, Oklahoma City
- Department of Geriatric Medicine, Translational Geroscience Laboratory (Z.U., S.T., A.C.), University of Oklahoma Health Sciences Center, Oklahoma City
| | - Anthony J Donato
- Division of Geriatrics, Department of Internal Medicine, University of Utah, Salt Lake City (A.J.D.)
- Veterans Affairs Medical Center-Salt Lake City, Geriatrics Research Education and Clinical Center, UT (A.J.D.)
| | - Veronica Galvan
- Barshop Institute for Longevity and Aging Studies (V.G.), University of Texas Health Science Center at San Antonio
- Department of Physiology (V.G.), University of Texas Health Science Center at San Antonio
| | - Anna Csiszar
- From the Vascular Cognitive Impairment Laboratory, Reynolds Oklahoma Center on Aging (Z.U., S.T., A.C.), University of Oklahoma Health Sciences Center, Oklahoma City
- Department of Geriatric Medicine, Translational Geroscience Laboratory (Z.U., S.T., A.C.), University of Oklahoma Health Sciences Center, Oklahoma City
- Department of Medical Physics and Informatics, University of Szeged, Hungary (Z.U., A.C.)
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Aldehyde Dehydrogenase 2 and Heart Failure. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1193:89-106. [PMID: 31368099 DOI: 10.1007/978-981-13-6260-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Heart failure (HF) is a structural or functional cardiac abnormal syndrome characterized with series of symptoms and signs such as breathlessness, fatigue, pulmonary crackles, and peripheral edema. Being a terminal phase of most myocardial lesions, HF has become a leading cause of mobility and mortality worldwide, associated with heavy clinical burden and economic costs affecting over 23 million people [14]. There is an increase to 5.5% with systolic dysfunction and an increase to 36.0% with diastolic dysfunction in people 60 years or older [85]. The costs accompanied with heart failure stand 2-3% of the total healthcare system expenditure in high-income countries and are expected to increase >2-fold in the next 2 decades [34].
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Abstract
Ageing is the main risk factor for the development of cardiovascular diseases. A central mechanism by which ageing promotes vascular pathologies is compromising endothelial health. The age-related attenuation of endothelium-dependent dilator responses (endothelial dysfunction) associated with impairment of angiogenic processes and the subsequent pathological remodelling of the microcirculation contribute to compromised tissue perfusion and exacerbate functional decline in older individuals. This Review focuses on cellular, molecular, and functional changes that occur in the endothelium during ageing. We explore the links between oxidative and nitrative stress and the conserved molecular pathways affecting endothelial dysfunction and impaired angiogenesis during ageing. We also speculate on how these pathological processes could be therapeutically targeted. An improved understanding of endothelial biology in older patients is crucial for all cardiologists because maintenance of a competently functioning endothelium is critical for adequate tissue perfusion and long-term cardiac health.
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Zhang L, Wang X, Cueto R, Effi C, Zhang Y, Tan H, Qin X, Ji Y, Yang X, Wang H. Biochemical basis and metabolic interplay of redox regulation. Redox Biol 2019; 26:101284. [PMID: 31400697 PMCID: PMC6831867 DOI: 10.1016/j.redox.2019.101284] [Citation(s) in RCA: 179] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 12/13/2022] Open
Abstract
Accumulated evidence strongly indicates that oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidants in favor of oxidants, plays an important role in disease pathogenesis. However, ROS can act as signaling molecules and fulfill essential physiological functions at basal levels. Each ROS would be different in the extent to stimulate and contribute to different pathophysiological effects. Importantly, multiple ROS generators can be activated either concomitantly or sequentially by relevant signaling molecules for redox biological functions. Here, we summarized the current knowledge related to chemical and biochemical features of primary ROS species and corresponding antioxidants. Metabolic pathways of five major ROS generators and five ROS clearance systems were described, including their ROS products, specific ROS enriched tissue, cell and organelle, and relevant functional implications. We provided an overview of ROS generation and induction at different levels of metabolism. We classified 11 ROS species into three types based on their reactivity and target selectivity and presented ROS homeostasis and functional implications in pathological and physiological status. This article intensively reviewed and refined biochemical basis, metabolic signaling and regulation, functional insights, and provided guidance for the identification of novel therapeutic targets.
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Affiliation(s)
- Lixiao Zhang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Xianwei Wang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Ramón Cueto
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Comfort Effi
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Yuling Zhang
- Cardiovascular Medicine Department, Sun Yat-sen Memorial Hospital, China
| | - Hongmei Tan
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, 510080, China
| | - Xuebin Qin
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Yong Ji
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China
| | - Xiaofeng Yang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, 19140, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
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Lv L, Ye W, Song P, Chen Y, Yang J, Zhang C, Chen X, Luo F. Relationship between ALDH2 genotype and in-stent restenosis in Chinese Han patients after percutaneous coronary intervention. BMC Cardiovasc Disord 2019; 19:176. [PMID: 31345174 PMCID: PMC6659264 DOI: 10.1186/s12872-019-1161-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 07/15/2019] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND It is well known that the genotype of ALDH2 is associated with coronary artery disease (CAD), and in-stent restenosis (ISR) is a primary complication of percutaneous coronary intervention (PCI), a primary recommended treatment for CAD. The aim of this study was to identify the relationship between aldehyde dehydrogenase 2 (ALDH2) genotype and in-stent restenosis (ISR). METHODS This study recruited 531 patients who were undergoing PCI at two Chinese hospitals from 2015 to 2017 and 183 were diagnosed with ISR after PCI during the one-year follow-up period. We used polymerase chain restriction fragment length polymorphism (PCR-RFLP) and sequencing to determine ALDH2 polymorphisms. RESULTS Among all 531 patients (mean age = 59.4 ± 9.8; 65.9% male), 68.7% carried the wild-type genotype, 28.4% were heterozygous for the mutation, and 2.8% were homozygous for the mutation. Multiple logistical regression analyses indicated no correlation between ALDH2 genotype and the occurrence of restenosis after PCI (OR = 1.448, 95% CI: 0.965-2.168, p = 0.073), though a significant association was observed for patients with diabetes (OR = 4.053, 95% CI: 1.668-10.449, p = 0.003). CONCLUSION In this study, we found that carrying an ALDH2*2 allele had no notable relationship with ISR one year after PCI but that it did have a significant association with complications in diabetic patients. Further studies with larger sample sizes will be necessary to reveal a consensus.
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Affiliation(s)
- Lizhi Lv
- Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008 People’s Republic of China
| | - Weijie Ye
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008 People’s Republic of China
| | - Peiyuan Song
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008 People’s Republic of China
| | - Yubin Chen
- Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008 People’s Republic of China
| | - Jing Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan People’s Republic of China
| | - Congmin Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan People’s Republic of China
| | - Xiaoping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008 People’s Republic of China
| | - Fanyan Luo
- Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008 People’s Republic of China
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Wagner DR, Karnik S, Gunderson ZJ, Nielsen JJ, Fennimore A, Promer HJ, Lowery JW, Loghmani MT, Low PS, McKinley TO, Kacena MA, Clauss M, Li J. Dysfunctional stem and progenitor cells impair fracture healing with age. World J Stem Cells 2019; 11:281-296. [PMID: 31293713 PMCID: PMC6600851 DOI: 10.4252/wjsc.v11.i6.281] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 06/13/2019] [Indexed: 02/06/2023] Open
Abstract
Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.
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Affiliation(s)
- Diane R Wagner
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Sonali Karnik
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Zachary J Gunderson
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jeffery J Nielsen
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States
| | - Alanna Fennimore
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Hunter J Promer
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - M Terry Loghmani
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Philip S Low
- Department of Chemistry, Purdue University, West Lafayette, IN 47907 United States
| | - Todd O McKinley
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, United States
| | - Matthias Clauss
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jiliang Li
- Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
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Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7092151. [PMID: 31341533 PMCID: PMC6612399 DOI: 10.1155/2019/7092151] [Citation(s) in RCA: 419] [Impact Index Per Article: 69.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 05/20/2019] [Indexed: 02/08/2023]
Abstract
Cardiovascular disease is a leading cause of death and reduced quality of life, proven by the latest data of the Global Burden of Disease Study, and is only gaining in prevalence worldwide. Clinical trials have identified chronic inflammatory disorders as cardiovascular risks, and recent research has revealed a contribution by various inflammatory cells to vascular oxidative stress. Atherosclerosis and cardiovascular disease are closely associated with inflammation, probably due to the close interaction of inflammation with oxidative stress. Classical therapies for inflammatory disorders have demonstrated protective effects in various models of cardiovascular disease; especially established drugs with pleiotropic immunomodulatory properties have proven beneficial cardiovascular effects; normalization of oxidative stress seems to be a common feature of these therapies. The close link between inflammation and redox balance was also supported by reports on aggravated inflammatory phenotype in the absence of antioxidant defense proteins (e.g., superoxide dismutases, heme oxygenase-1, and glutathione peroxidases) or overexpression of reactive oxygen species producing enzymes (e.g., NADPH oxidases). The value of immunomodulation for the treatment of cardiovascular disease was recently supported by large-scale clinical trials demonstrating reduced cardiovascular mortality in patients with established atherosclerotic disease when treated by highly specific anti-inflammatory therapies (e.g., using monoclonal antibodies against cytokines). Modern antidiabetic cardiovascular drugs (e.g., SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 analogs) seem to share these immunomodulatory properties and display potent antioxidant effects, all of which may explain their successful lowering of cardiovascular risk.
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Aldehyde Dehydrogenase 2 (ALDH2) and Aging: Is There a Sensible Link? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1193:237-253. [DOI: 10.1007/978-981-13-6260-6_15] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Tejero J, Shiva S, Gladwin MT. Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation. Physiol Rev 2019; 99:311-379. [PMID: 30379623 PMCID: PMC6442925 DOI: 10.1152/physrev.00036.2017] [Citation(s) in RCA: 330] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 03/30/2018] [Accepted: 05/06/2018] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology. The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of adequate blood flow is critical to the healthy performance of the vasculature. A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia. At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism. NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes. The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite. Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreductases and determine the redox balance in health and disease. The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy. In this review we will present the biology of NO and ROS in the cardiovascular system, with special emphasis on their routes of formation and regulation, as well as the therapeutic challenges and opportunities for the management of NO and ROS in cardiovascular disease.
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Affiliation(s)
- Jesús Tejero
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Sruti Shiva
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Mark T Gladwin
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
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Rossman MJ, LaRocca TJ, Martens CR, Seals DR. Healthy lifestyle-based approaches for successful vascular aging. J Appl Physiol (1985) 2018; 125:1888-1900. [PMID: 30212305 PMCID: PMC6842891 DOI: 10.1152/japplphysiol.00521.2018] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 08/23/2018] [Accepted: 09/09/2018] [Indexed: 12/19/2022] Open
Abstract
This review summarizes a presentation given at the 2016 Gerontological Society of America Annual Meeting as part of the Vascular Aging Workshop. The development of age-related vascular dysfunction increases the risk of cardiovascular disease as well as other chronic age-associated disorders, including chronic kidney disease and Alzheimer's disease. Healthy lifestyle behaviors, most notably regular aerobic exercise and certain dietary patterns, are considered "first-line" strategies for the prevention and/or treatment of vascular dysfunction with aging. Despite the well-established benefits of these strategies, however, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related vascular dysfunction. Time-efficient forms of exercise training, hormetic exposure to mild environmental stress, fasting "mimicking" dietary paradigms, and nutraceutical/pharmaceutical approaches to favorably modulate cellular and molecular pathways activated by exercise and healthy dietary patterns may hold promise as such alternative approaches. Determining the efficacy of these novel strategies is important to provide alternatives for adults with low adherence to conventional healthy lifestyle practices for healthy vascular aging.
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Affiliation(s)
- Matthew J Rossman
- Department of Integrative Physiology, University of Colorado-Boulder , Boulder, Colorado
| | - Thomas J LaRocca
- Department of Integrative Physiology, University of Colorado-Boulder , Boulder, Colorado
| | - Christopher R Martens
- Department of Integrative Physiology, University of Colorado-Boulder , Boulder, Colorado
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado-Boulder , Boulder, Colorado
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Larosa V, Remacle C. Insights into the respiratory chain and oxidative stress. Biosci Rep 2018; 38:BSR20171492. [PMID: 30201689 PMCID: PMC6167499 DOI: 10.1042/bsr20171492] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 08/15/2018] [Accepted: 09/05/2018] [Indexed: 01/13/2023] Open
Abstract
Reactive oxygen species (ROS) are highly reactive reduced oxygen molecules that result from aerobic metabolism. The common forms are the superoxide anion (O2∙-) and hydrogen peroxide (H2O2) and their derived forms, hydroxyl radical (HO∙) and hydroperoxyl radical (HOO∙). Their production sites in mitochondria are reviewed. Even though being highly toxic products, ROS seem important in transducing information from dysfunctional mitochondria. Evidences of signal transduction mediated by ROS in mitochondrial deficiency contexts are then presented in different organisms such as yeast, mammals or photosynthetic organisms.
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Affiliation(s)
- Véronique Larosa
- Genetics and Physiology of Microalgae, UR InBios/Phytosystems, Chemin de la Vallée, 4, University of Liège, Liège 4000, Belgium
| | - Claire Remacle
- Genetics and Physiology of Microalgae, UR InBios/Phytosystems, Chemin de la Vallée, 4, University of Liège, Liège 4000, Belgium
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Nikray N, Karimi I, Siavashhaghighi Z, Becker LA, Mofatteh MM. An effort toward molecular biology of food deprivation induced food hoarding in gonadectomized NMRI mouse model: focus on neural oxidative status. BMC Neurosci 2018; 19:59. [PMID: 30249177 PMCID: PMC6154416 DOI: 10.1186/s12868-018-0461-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 09/20/2018] [Indexed: 12/03/2022] Open
Abstract
Background Environmental uncertainty, such as food deprivation, may alter internal milieu of nervous system through various mechanisms. In combination with circumstances of stress or aging, high consumption of unsaturated fatty acids and oxygen can make neural tissues sensitive to oxidative stress (OS). For adult rats, diminished level of gonadal steroid hormones accelerates OS and may result in special behavioral manifestations. This study was aimed to partially answer the question whether OS mediates trade-off between food hoarding and food intake (fat hoarding) in environmental uncertainty (e.g., fluctuations in food resource) within gonadectomized mouse model in the presence of food deprivation-induced food hoarding behavior. Results Hoarding behavior was not uniformly expressed in all male mice that exposed to food deprivation. Extended phenotypes including hoarder and non-hoarder mice stored higher and lower amounts of food respectively as compared to that of low-hoarder mice (normal phenotype) after food deprivation. Results showed that neural oxidative status was not changed in the presence of hoarding behavior in gonadectomized mice regardless of tissue type, however, glutathione levels of brain tissues were increased in the presence of hoarding behavior. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde in brain tissues of gonadectomized mice were also seen. Conclusions Although, food deprivation-induced hoarding behavior is a strategic response to food shortage in mice, it did not induce the same amount of hoarding across all colony mates. Hoarding behavior, in this case, is a response to the environmental uncertainty of food shortage, therefore is not an abnormal behavior. Hoarding behavior induced neural OS with regard to an increase in brain glutathione levels but failed to show other markers of neural OS. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde levels in brain tissues of gonadectomized mice could be a hallmark of debilitated antioxidative defense and more lipid peroxidation due to reduced amount of gonadal steroid hormones during aging.
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Affiliation(s)
- Noushin Nikray
- Laboratory of Molecular and Cellular Biology 1214, Department of Basic Veterinary Sciences, School of Veterinary Medicine, Razi University, Kermanshah, Iran
| | - Isaac Karimi
- Laboratory of Molecular and Cellular Biology 1214, Department of Basic Veterinary Sciences, School of Veterinary Medicine, Razi University, Kermanshah, Iran. .,Department of Biology, Faculty of Science, Razi University, Kermanshah, 67149-67346, Iran.
| | | | - Lora A Becker
- Department of Psychology, University of Evansville, Evansville, IN, 47722, USA
| | - Mohammad Mehdi Mofatteh
- Department of Accounting, School of Economics and Accounting, Islamic Azad University South Tehran Branch, Tehran, Iran
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Seals DR, Brunt VE, Rossman MJ. Keynote lecture: strategies for optimal cardiovascular aging. Am J Physiol Heart Circ Physiol 2018; 315:H183-H188. [PMID: 29652545 PMCID: PMC6139621 DOI: 10.1152/ajpheart.00734.2017] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/09/2018] [Accepted: 04/09/2018] [Indexed: 12/19/2022]
Abstract
This review summarizes the opening keynote presentation overview of the American Physiological Society Conference on Cardiovascular Aging: New Frontiers and Old Friends held in Westminster, CO, in August 2017. Age is the primary risk factor for cardiovascular diseases (CVDs). Without effective intervention, future increases in the number of older adults will translate to a greater prevalence of CVDs and related disorders. Advancing age increases the risk of CVDs partly via direct effects on the heart and through increases in blood pressure; however, much of the risk is mediated by vascular dysfunction, including large elastic artery stiffening and both macro- and microvascular endothelial dysfunction. Although excessive superoxide-related oxidative stress and chronic low-grade inflammation are the major processes driving cardiovascular aging, the upstream mechanisms involved represent new frontiers of investigation and potential therapeutic targets. Lifestyle practices, including aerobic exercise, energy intake (caloric) restriction, and healthy diet composition, are the most evidence-based strategies (old friends) for optimal cardiovascular aging, but adherence is poor in some groups. Healthy lifestyle "mimicking" approaches, including novel forms of physical training, intermittent fasting paradigms, exercise/healthy diet-inspired nutraceuticals (functional foods and natural supplements), as well as controlled environmental stress exposure (e.g., heat therapy), may hold promise but are unproven. Mitigating the adverse effects of aging on cardiovascular function and health is a high biomedical priority.
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Affiliation(s)
- Douglas R Seals
- Department of Integrative Physiology University of Colorado Boulder , Boulder, Colorado
| | - Vienna E Brunt
- Department of Integrative Physiology University of Colorado Boulder , Boulder, Colorado
| | - Matthew J Rossman
- Department of Integrative Physiology University of Colorado Boulder , Boulder, Colorado
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Carvalho C, Moreira PI. Oxidative Stress: A Major Player in Cerebrovascular Alterations Associated to Neurodegenerative Events. Front Physiol 2018; 9:806. [PMID: 30018565 PMCID: PMC6037979 DOI: 10.3389/fphys.2018.00806] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 06/08/2018] [Indexed: 12/19/2022] Open
Abstract
The brain is one of the most exquisite organs in the body with high metabolic demands, and requires a tight regulation of the surrounding environment. This tight control is exerted by the neurovascular unit (NVU) comprising different cell types, where endothelial cells play the commander-in-chief role. Thus, it is assumable that even slight perturbations in NVU might affect, in some cases irreversibly, brain homeostasis and health. In this line, recent findings support the two-hit vascular hypothesis for neurodegenerative conditions, where vascular dysfunction underlies the development of neurodegenerative diseases, such as Alzheimer’s disease (AD). Knowing that endothelial cells are rich in mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, two major reactive oxygen species (ROS) sources, this review aims to gather information on how oxidative stress is in the front line of vascular alterations observed in brain aging and neurodegenerative conditions, particularly AD. Also, a brief discussion about the therapeutic strategies aimed to protect against cerebrovascular diseases is included.
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Affiliation(s)
- Cristina Carvalho
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Paula I Moreira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
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