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1
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Mastoor Y, Murphy E, Roman B. Mechanisms of postischemic cardiac death and protection following myocardial injury. J Clin Invest 2025; 135:e184134. [PMID: 39744953 DOI: 10.1172/jci184134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a "drug cocktail" approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.
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2
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Erman A, Hawkins LJ, Storey KB. Changes in microRNA expression related to ischemia-reperfusion injury in the kidney of the thirteen-lined ground squirrel during torpor. Biochimie 2024; 225:40-48. [PMID: 38705508 DOI: 10.1016/j.biochi.2024.05.001] [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: 02/11/2024] [Revised: 04/18/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
During the hibernation season, the thirteen-lined ground squirrel undergoes cyclical torpor and arousal periods. The decrease and restoration of metabolic rate and oxygen delivery during torpor and arousal, respectively, may cause reperfusion-ischemia injury in the kidneys. In order to maintain the structural integrity of the kidneys necessary for renal function resumption during arousal, the thirteen-lined ground squirrel has developed adaptive methods to prevent and repair kidney injury. In this present study, computational methods were used to clean and analyze sequenced kidney RNA samples. Significantly differentially expressed microRNAs and enriched gene sets were also determined. From the gene set analysis, the results showed an increase in ubiquitin-related processes and p53 signaling pathways which suggested the occurrence of kidney damage during torpor. There was also an observed increase in cell cycle processes and the anchoring junction cellular compartment which may lend to the prevention of kidney injury. From the differentially expressed microRNAs, miR-27a (log2FC = 1.639; p-value = 0.023), miR-129 (log2FC = 2.516; p-value = 0.023), miR-let-7b (log2FC = 2.360; p-value = 0.025), miR-let-7c (log2FC = 2.291; p-value = 0.037) and miR-let-7i (log2FC = 1.564; p-value = 0.039) were found to be significantly upregulated. These biochemical adaptations may allow the thirteen-lined ground squirrel to maintain kidney structure and function during hibernation.
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Affiliation(s)
- Aylin Erman
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada.
| | - Liam J Hawkins
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada
| | - Kenneth B Storey
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada
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Pyrpyris N, Dimitriadis K, Iliakis P, Theofilis P, Beneki E, Terentes-Printzios D, Sakalidis A, Antonopoulos A, Aznaouridis K, Tsioufis K. Hypothermia for Cardioprotection in Acute Coronary Syndrome Patients: From Bench to Bedside. J Clin Med 2024; 13:5390. [PMID: 39336877 PMCID: PMC11432135 DOI: 10.3390/jcm13185390] [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: 08/18/2024] [Revised: 09/05/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
Early revascularization for patients with acute myocardial infarction (AMI) is of outmost importance in limiting infarct size and associated complications, as well as for improving long-term survival and outcomes. However, reperfusion itself may further damage the myocardium and increase the infarct size, a condition commonly recognized as myocardial reperfusion injury. Several strategies have been developed for limiting the associated with reperfusion myocardial damage, including hypothermia. Hypothermia has been shown to limit the degree of infarct size increase, when started before reperfusion, in several animal models. Systemic hypothermia, however, failed to show any benefit, due to adverse events and potentially insufficient myocardial cooling. Recently, the novel technique of intracoronary selective hypothermia is being tested, with preclinical and clinical results being of particular interest. Therefore, in this review, we will describe the pathophysiology of myocardial reperfusion injury and the cardioprotective mechanics of hypothermia, report the animal and clinical evidence in both systemic and selective hypothermia and discuss the potential future directions and clinical perspectives in the context of cardioprotection for myocardial reperfusion injury.
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Affiliation(s)
| | - Kyriakos Dimitriadis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27 Athens, Greece; (N.P.); (P.I.); (P.T.); (E.B.); (D.T.-P.); (A.S.); (A.A.); (K.A.); (K.T.)
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Cohen MV, Downey JM. Initial Despair and Current Hope of Identifying a Clinically Useful Treatment of Myocardial Reperfusion Injury: Insights Derived from Studies of Platelet P2Y 12 Antagonists and Interference with Inflammation and NLRP3 Assembly. Int J Mol Sci 2024; 25:5477. [PMID: 38791515 PMCID: PMC11122283 DOI: 10.3390/ijms25105477] [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: 03/28/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.
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Affiliation(s)
- Michael V. Cohen
- The Departments of Physiology and Cell Biology, Frederick P. Whiddon College of Medicine, Mobile, AL 36688, USA;
- The Departments of Medicine, Frederick P. Whiddon College of Medicine, Mobile, AL 36688, USA
| | - James M. Downey
- The Departments of Physiology and Cell Biology, Frederick P. Whiddon College of Medicine, Mobile, AL 36688, USA;
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5
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Galli M, Niccoli G, De Maria G, Brugaletta S, Montone RA, Vergallo R, Benenati S, Magnani G, D'Amario D, Porto I, Burzotta F, Abbate A, Angiolillo DJ, Crea F. Coronary microvascular obstruction and dysfunction in patients with acute myocardial infarction. Nat Rev Cardiol 2024; 21:283-298. [PMID: 38001231 DOI: 10.1038/s41569-023-00953-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/23/2023] [Indexed: 11/26/2023]
Abstract
Despite prompt epicardial recanalization in patients presenting with ST-segment elevation myocardial infarction (STEMI), coronary microvascular obstruction and dysfunction (CMVO) is still fairly common and is associated with poor prognosis. Various pharmacological and mechanical strategies to treat CMVO have been proposed, but the positive results reported in preclinical and small proof-of-concept studies have not translated into benefits in large clinical trials conducted in the modern treatment setting of patients with STEMI. Therefore, the optimal management of these patients remains a topic of debate. In this Review, we appraise the pathophysiological mechanisms of CMVO, explore the evidence and provide future perspectives on strategies to be implemented to reduce the incidence of CMVO and improve prognosis in patients with STEMI.
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Affiliation(s)
- Mattia Galli
- Department of Cardiology, Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy
| | | | - Gianluigi De Maria
- Oxford Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Salvatore Brugaletta
- Institut Clinic Cardiovascular, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
| | - Rocco A Montone
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Rocco Vergallo
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, Genova, Italy
| | - Stefano Benenati
- Oxford Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, Genova, Italy
| | - Giulia Magnani
- Department of Cardiology, University of Parma, Parma, Italy
| | - Domenico D'Amario
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
- Division of Cardiology, Azienda Ospedaliero Universitaria 'Maggiore Della Carita', Novara, Italy
| | - Italo Porto
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, Genova, Italy
| | - Francesco Burzotta
- Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Cardiovascular Sciencies, Catholic University of the Sacred Heart, Rome, Italy
| | - Antonio Abbate
- Robert M. Berne Cardiovascular Research Center, Division of Cardiology - Heart and Vascular Center, University of Virginia, Charlottesville, VA, USA
| | - Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine - Jacksonville, Jacksonville, FL, USA.
| | - Filippo Crea
- Department of Cardiovascular Sciencies, Catholic University of the Sacred Heart, Rome, Italy
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Bollen Pinto B, Ackland GL. Pathophysiological mechanisms underlying increased circulating cardiac troponin in noncardiac surgery: a narrative review. Br J Anaesth 2024; 132:653-666. [PMID: 38262855 DOI: 10.1016/j.bja.2023.12.017] [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: 06/12/2023] [Revised: 11/23/2023] [Accepted: 12/15/2023] [Indexed: 01/25/2024] Open
Abstract
Assay-specific increases in circulating cardiac troponin are observed in 20-40% of patients after noncardiac surgery, depending on patient age, type of surgery, and comorbidities. Increased cardiac troponin is consistently associated with excess morbidity and mortality after noncardiac surgery. Despite these findings, the underlying mechanisms are unclear. The majority of interventional trials have been designed on the premise that ischaemic cardiac disease drives elevated perioperative cardiac troponin concentrations. We consider data showing that elevated circulating cardiac troponin after surgery could be a nonspecific marker of cardiomyocyte stress. Elevated concentrations of circulating cardiac troponin could reflect coordinated pathological processes underpinning organ injury that are not necessarily caused by ischaemia. Laboratory studies suggest that matching of coronary artery autoregulation and myocardial perfusion-contraction coupling limit the impact of systemic haemodynamic changes in the myocardium, and that type 2 ischaemia might not be the likeliest explanation for cardiac troponin elevation in noncardiac surgery. The perioperative period triggers multiple pathological mechanisms that might cause cardiac troponin to cross the sarcolemma. A two-hit model involving two or more triggers including systemic inflammation, haemodynamic strain, adrenergic stress, and autonomic dysfunction might exacerbate or initiate acute myocardial injury directly in the absence of cell death. Consideration of these diverse mechanisms is pivotal for the design and interpretation of interventional perioperative trials.
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Affiliation(s)
- Bernardo Bollen Pinto
- Division of Anaesthesiology, Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.
| | - Gareth L Ackland
- Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK
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7
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Ding X, Zhu C, Wang W, Li M, Ma C, Gao B. SIRT1 is a regulator of autophagy: Implications for the progression and treatment of myocardial ischemia-reperfusion. Pharmacol Res 2024; 199:106957. [PMID: 37820856 DOI: 10.1016/j.phrs.2023.106957] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 09/09/2023] [Accepted: 10/08/2023] [Indexed: 10/13/2023]
Abstract
SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. It is involved in the regulation of various pathophysiological processes, including cell proliferation, survival, differentiation, autophagy, and oxidative stress. Therapeutic activation of SIRT1 protects the heart and cardiomyocytes from pathology-related stress, particularly myocardial ischemia/reperfusion (I/R). Autophagy is an important metabolic pathway for cell survival during energy or nutrient deficiency, hypoxia, or oxidative stress. Autophagy is a double-edged sword in myocardial I/R injury. The activation of autophagy during the ischemic phase removes excess metabolic waste and helps ensure cardiomyocyte survival, whereas excessive autophagy during reperfusion depletes the cellular components and leads to autophagic cell death. Increasing research on I/R injury has indicated that SIRT1 is involved in the process of autophagy and regulates myocardial I/R. SIRT1 regulates autophagy through various pathways, such as the deacetylation of FOXOs, ATGs, and LC3. Recent studies have confirmed that SIRT1-mediated autophagy plays different roles at different stages of myocardial I/R injury. By targeting the mechanism of SIRT1-mediated autophagy at different stages of I/R injury, new small-molecule drugs, miRNA activators, or blockers can be developed. For example, resveratrol, sevoflurane, quercetin, and melatonin in the ischemic stage, coptisine, curcumin, berberine, and some miRNAs during reperfusion, were involved in regulating the SIRT1-autophagy axis, exerting a cardioprotective effect. Here, we summarize the possible mechanisms of autophagy regulation by SIRT1 in myocardial I/R injury and the related molecular drug applications to identify strategies for treating myocardial I/R injury.
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Affiliation(s)
- Xiaoqing Ding
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Chenyu Zhu
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Wenhong Wang
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Mengying Li
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Chunwei Ma
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China
| | - Binghong Gao
- School of Athletic Performance, Shanghai University of Sport, Shanghai 200438, China.
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8
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Kraler S, Balbi C, Vdovenko D, Lapikova-Bryhinska T, Camici GG, Liberale L, Bonetti N, Canestro CD, Burger F, Roth A, Carbone F, Vassalli G, Mach F, Bhasin S, Wenzl FA, Muller O, Räber L, Matter CM, Montecucco F, Lüscher TF, Akhmedov A. Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans. Cardiovasc Res 2023; 119:2729-2742. [PMID: 37742057 PMCID: PMC10757585 DOI: 10.1093/cvr/cvad153] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/18/2023] [Accepted: 09/04/2023] [Indexed: 09/25/2023] Open
Abstract
AIMS The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing. METHODS AND RESULTS In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels. CONCLUSION Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.
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Affiliation(s)
- Simon Kraler
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
| | - Carolina Balbi
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
- Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Institute, EOC, Lugano, Switzerland
- Laboratories for Translational Research, EOC, Bellinzona, Switzerland
| | - Daria Vdovenko
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
| | | | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genova—Italian Cardiovascular Network, Genoa, Italy
| | - Nicole Bonetti
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
- University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Candela Diaz Canestro
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
| | - Fabienne Burger
- Division of Cardiology, Foundation for Medical Research, University of Geneva, Geneva, Switzerland
| | - Aline Roth
- Division of Cardiology, Foundation for Medical Research, University of Geneva, Geneva, Switzerland
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genova—Italian Cardiovascular Network, Genoa, Italy
| | - Giuseppe Vassalli
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
- Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Institute, EOC, Lugano, Switzerland
- Laboratories for Translational Research, EOC, Bellinzona, Switzerland
| | - François Mach
- Division of Cardiology, Foundation for Medical Research, University of Geneva, Geneva, Switzerland
| | - Shalender Bhasin
- Research Program in Men's Health: Aging and Metabolism, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
| | - Florian A Wenzl
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
| | - Olivier Muller
- Department of Cardiology, University Hospital of Lausanne, University of Lausanne, Lausanne, Switzerland
| | - Lorenz Räber
- Department of Cardiology, Inselspital Bern, Bern, Switzerland
| | - Christian M Matter
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
- University Heart Center, Cardiology, University Hospital Zurich, Zurich, Switzerland
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genova—Italian Cardiovascular Network, Genoa, Italy
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
- Royal Brompton and Harefield Hospitals and Imperial College and Kings College, London, UK
| | - Alexander Akhmedov
- Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Zurich CH-8952, Switzerland
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Chen Z, Cheng Z, Ding C, Cao T, Chen L, Wang H, Li J, Huang X. ROS-Activated TRPM2 Channel: Calcium Homeostasis in Cardiovascular/renal System and Speculation in Cardiorenal Syndrome. Cardiovasc Drugs Ther 2023:10.1007/s10557-023-07531-3. [PMID: 38108918 DOI: 10.1007/s10557-023-07531-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/20/2023] [Indexed: 12/19/2023]
Abstract
The transient receptor potential melastatin 2 (TRPM2) channel is a nonselective calcium channel that is sensitive to oxidative stress (OS), and is widely expressed in multiple organs, such as the heart, kidney, and brain, which is inextricably related to calcium dyshomeostasis and downstream pathological events. Due to the increasing global burden of kidney or cardiovascular diseases (CVDs), safe and efficient drugs specific to novel targets are imperatively needed. Notably, investigation of the possibility to regard the TRPM2 channel as a new therapeutic target in ROS-related CVDs or renal diseases is urgently required because the roles of the TRPM2 channel in heart or kidney diseases have not received enough attention and thus have not been fully elaborated. Therefore, we aimed to review the involvement of the TRPM2 channel in cardiovascular disorders related to kidney or typical renal diseases and attempted to speculate about TRPM2-mediated mechanisms of cardiorenal syndrome (CRS) to provide representative perspectives for future research about novel and effective therapeutic strategies.
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Affiliation(s)
- Zihan Chen
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
- Queen Mary School, Medical Department, Nanchang University, Nanchang, China
| | - Zaihua Cheng
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Congcong Ding
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Tianyu Cao
- Biological anthropology, University of California, Santa Barbara, CA, USA
| | - Ling Chen
- Department of Cardiology, the First People's Hospital of Jiujiang, Jiujiang, China
| | - Hong Wang
- Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Junpei Li
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China.
| | - Xiao Huang
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China.
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10
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Xiao Z, Wei X, Li M, Yang K, Chen R, Su Y, Yu Z, Liang Y, Ge J. Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation. J Mol Cell Cardiol 2023; 183:54-66. [PMID: 37689005 DOI: 10.1016/j.yjmcc.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/29/2023] [Accepted: 08/29/2023] [Indexed: 09/11/2023]
Abstract
BACKGROUND Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI. METHODS MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury. RESULTS Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury. CONCLUSION This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.
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Affiliation(s)
- Zilong Xiao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China
| | - Xiang Wei
- Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Minghui Li
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Kun Yang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China
| | - Ruizhen Chen
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Yangang Su
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Ziqing Yu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Yixiu Liang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China.
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China
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Qin H, Zhou J. Myocardial Protection by Desflurane: From Basic Mechanisms to Clinical Applications. J Cardiovasc Pharmacol 2023; 82:169-179. [PMID: 37405905 DOI: 10.1097/fjc.0000000000001448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 06/15/2023] [Indexed: 07/07/2023]
Abstract
ABSTRACT Coronary heart disease is an affliction that is common and has an adverse effect on patients' quality of life and survival while also raising the risk of intraoperative anesthesia. Mitochondria are the organelles most closely associated with the pathogenesis, development, and prognosis of coronary heart disease. Ion abnormalities, an acidic environment, the production of reactive oxygen species, and other changes during abnormal myocardial metabolism cause the opening of mitochondrial permeability transition pores, which disrupts electron transport, impairs mitochondrial function, and even causes cell death. Differences in reliability and cost-effectiveness between desflurane and other volatile anesthetics are minor, but desflurane has shown better myocardial protective benefits in the surgical management of patients with coronary artery disease. The results of myocardial protection by desflurane are briefly summarized in this review, and biological functions of the mitochondrial permeability transition pore, mitochondrial electron transport chain, reactive oxygen species, adenosine triphosphate-dependent potassium channels, G protein-coupled receptors, and protein kinase C are discussed in relation to the protective mechanism of desflurane. This article also discusses the effects of desflurane on patient hemodynamics, myocardial function, and postoperative parameters during coronary artery bypass grafting. Although there are limited and insufficient clinical investigations, they do highlight the possible advantages of desflurane and offer additional suggestions for patients.
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Affiliation(s)
- Han Qin
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, China
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12
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Xu Q, Cheung RTF. Melatonin mitigates type 1 diabetes-aggravated cerebral ischemia-reperfusion injury through anti-inflammatory and anti-apoptotic effects. Brain Behav 2023; 13:e3118. [PMID: 37327371 PMCID: PMC10498092 DOI: 10.1002/brb3.3118] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 05/15/2023] [Accepted: 05/31/2023] [Indexed: 06/18/2023] Open
Abstract
INTRODUCTION Cerebral ischemia and diabetes mellitus (DM) are common diseases that often coexist and interact with each other. DM doubles the risk of ischemic stroke, and cerebral ischemia causes stress-induced hyperglycemia. Most experimental stroke studies used healthy animals. Melatonin is neuroprotective against cerebral ischemia-reperfusion injury (CIRI) in non-DM, normoglycemic animals through anti-oxidant effect, anti-inflammation, and anti-apoptosis. Previous studies have also reported a negative correlation between hyperglycemia and urinary melatonin metabolite. OBJECTIVES The present study investigated the effects of type 1 DM (T1DM) on CIRI in rats and the role of melatonin against CIRI in T1DM animals. RESULTS Our results revealed that T1DM aggravated CIRI, leading to greater weight loss, increased infarct volume, and worse neurological deficit. T1DM aggravated the post-CIRI activation of nuclear factor kappa B (NF-κB) pathway and increase in pro-apoptotic markers. A single intraperitoneal injection of melatonin at 10 mg/kg given 30 min before ischemia onset attenuated CIRI in T1DM rats, resulting in less weight loss, decreased infarct volume, and milder neurological deficit when compared with the vehicle group. Melatonin treatment achieved anti-inflammatory and anti-apoptotic effects with reduced NF-κB pathway activation, reduced mitochondrial cytochrome C release, decreased calpain-mediated spectrin breakdown product (SBDP), and decreased caspase-3-mediated SBDP. The treatment also led to fewer iNOS+ cells, milder CD-68+ macrophage/microglia infiltration, decreased TUNEL+ apoptotic cells, and better neuronal survival. CONCLUSIONS T1DM aggravates CIRI. Melatonin treatment is neuroprotective against CIRI in T1DM rats via anti-inflammatory and anti-apoptotic effects.
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Affiliation(s)
- Qian Xu
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Raymond Tak Fai Cheung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
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Li N, Gu X, Liu F, Zhang Y, Sun Y, Gao S, Wang B, Zhang C. Network pharmacology-based analysis of potential mechanisms of myocardial ischemia-reperfusion injury by total salvianolic acid injection. Front Pharmacol 2023; 14:1202718. [PMID: 37680709 PMCID: PMC10482107 DOI: 10.3389/fphar.2023.1202718] [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: 04/09/2023] [Accepted: 08/11/2023] [Indexed: 09/09/2023] Open
Abstract
In this review, we investigated the potential mechanism of Total Salvianolic Acid Injection (TSI) in protecting against myocardial ischemia reperfusion injury (MI/RI). To achieve this, we predicted the component targets of TSI using Pharmmapper and identified the disease targets of MI/RI through GeneCards, DisGenNET, and OMIM databases. We constructed protein-protein interaction networks by analyzing the overlapping targets and performed functional enrichment analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Our analysis yielded 90 targets, which were implicated in the potential therapeutic effects of TSI on MI/RI. Seven critical signaling pathways significantly contributed to TSI's protective effects, namely, PI3K signaling, JAK-STAT signaling, Calcium signaling, HIF-1 signaling, Nuclear receptor signaling, Cell Cycle, and Apoptosis. Subsequently, we conducted a comprehensive literature review of these seven key signaling pathways to gain further insights into their role in the TSI-mediated treatment of MI/RI. By establishing these connections, our study lays a solid foundation for future research endeavours to elucidate the molecular mechanisms through which TSI exerts its beneficial effects on MI/RI.
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Affiliation(s)
- Nan Li
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Xufang Gu
- The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fanqi Liu
- The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yao Zhang
- The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanjun Sun
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Shengwei Gao
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Baohe Wang
- The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chen Zhang
- The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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14
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Pradegan N, Gallo M, Fabozzo A, Toscano G, Tarzia V, Gerosa G. Nonischemic Donor Heart Preservation: New Milestone in Heart Transplantation History. ASAIO J 2023; 69:725-733. [PMID: 37319037 DOI: 10.1097/mat.0000000000002001] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023] Open
Abstract
Heart transplantation is considered the gold standard for the treatment of advanced end-stage heart failure. However, standard donors after brain death are decreasing, whereas patients on the heart transplant waitlist are constantly rising. The introduction of the ex vivo machine perfusion device has been a turning point; in fact, these systems are able to significantly reduce ischemic times and have a potential effect on ischemia-related damage reduction. From a clinical standpoint, these machines show emerging results in terms of heart donor pool expansion, making marginal donors and donor grafts after circulatory death suitable for donation. This article aims to review mechanisms and preclinical and clinical outcomes of currently available ex vivo perfusion systems, and to explore the future fields of application of these technologies.
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Affiliation(s)
- Nicola Pradegan
- From the Cardiac Surgery Unit, Heart Transplantation Program, Cardiac, Thoracic, Vascular Sciences and Public Health Department, Padova University Hospital, Padova, Italy
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15
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Kudryashev JA, Madias MI, Kandell RM, Lin QX, Kwon EJ. An Activity-Based Nanosensor for Minimally-Invasive Measurement of Protease Activity in Traumatic Brain Injury. ADVANCED FUNCTIONAL MATERIALS 2023; 33:2300218. [PMID: 37873031 PMCID: PMC10586543 DOI: 10.1002/adfm.202300218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Indexed: 10/25/2023]
Abstract
Current screening and diagnostic tools for traumatic brain injury (TBI) have limitations in sensitivity and prognostication. Aberrant protease activity is a central process that drives disease progression in TBI and is associated with worsened prognosis; thus direct measurements of protease activity could provide more diagnostic information. In this study, a nanosensor is engineered to release a measurable signal into the blood and urine in response to activity from the TBI-associated protease calpain. Readouts from the nanosensor were designed to be compatible with ELISA and lateral flow assays, clinically-relevant assay modalities. In a mouse model of TBI, the nanosensor sensitivity is enhanced when ligands that target hyaluronic acid are added. In evaluation of mice with mild or severe injuries, the nanosensor identifies mild TBI with a higher sensitivity than the biomarker GFAP. This nanosensor technology allows for measurement of TBI-associated proteases without the need to directly access brain tissue, and has the potential to complement existing TBI diagnostic tools.
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Affiliation(s)
- Julia A Kudryashev
- Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States
| | - Marianne I Madias
- Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States
| | - Rebecca M Kandell
- Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States
| | - Queenie X Lin
- Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States
| | - Ester J Kwon
- Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, United States
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16
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Popov LD. Mitochondria as intracellular signalling organelles. An update. Cell Signal 2023:110794. [PMID: 37422005 DOI: 10.1016/j.cellsig.2023.110794] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/23/2023] [Accepted: 07/02/2023] [Indexed: 07/10/2023]
Abstract
Traditionally, mitochondria are known as "the powerhouse of the cell," responsible for energy (ATP) generation (by the electron transport chain, oxidative phosphorylation, the tricarboxylic acid cycle, and fatty acid ß-oxidation), and for the regulation of several metabolic processes, including redox homeostasis, calcium signalling, and cellular apoptosis. The extensive studies conducted in the last decades portray mitochondria as multifaceted signalling organelles that ultimately command cells' survival or death. Based on current knowledge, we'll outline the mitochondrial signalling to other intracellular compartments in homeostasis and pathology-related mitochondrial stress conditions here. The following topics are discussed: (i) oxidative stress and mtROS signalling in mitohormesis, (ii) mitochondrial Ca2+ signalling; (iii) the anterograde (nucleus-to-mitochondria) and retrograde (mitochondria-to-nucleus) signal transduction, (iv) the mtDNA role in immunity and inflammation, (v) the induction of mitophagy- and apoptosis - signalling cascades, (vi) the mitochondrial dysfunctions (mitochondriopathies) in cardiovascular, neurodegenerative, and malignant diseases. The novel insights into molecular mechanisms of mitochondria-mediated signalling can explain mitochondria adaptation to metabolic and environmental stresses to achieve cell survival.
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Affiliation(s)
- Lucia-Doina Popov
- Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8, B.P. Hasdeu Street, 050568 Bucharest, Romania.
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17
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Pang Q, You L, Meng X, Li Y, Deng T, Li D, Zhu B. Regulation of the JAK/STAT signaling pathway: The promising targets for cardiovascular disease. Biochem Pharmacol 2023; 213:115587. [PMID: 37187275 DOI: 10.1016/j.bcp.2023.115587] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/17/2023]
Abstract
Individuals have known that Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway was involved in the growth of the cell, cell differentiation courses advancement, immune cellular survival, as well as hematopoietic system advancement. Researches in the animal models have already uncovered a JAK/STAT regulatory function in myocardial ischemia-reperfusion injury (MIRI), acute myocardial infarction (MI), hypertension, myocarditis, heart failure, angiogenesis and fibrosis. Evidences originating in these studies indicate a therapeutic JAK/STAT function in cardiovascular diseases (CVDs). In this retrospection, various JAK/STAT functions in the normal and ill hearts were described. Moreover, the latest figures about JAK/STAT were summarized under the background of CVDs. Finally, we discussed the clinical transformation prospects and technical limitations of JAK/STAT as the potential therapeutic targets for CVDs. This collection of evidences has essential meanings for the clinical application of JAK/STAT as medicinal agents for CVDs. In this retrospection, various JAK/STAT functions in the normal and ill hearts were described. Moreover, the latest figures about JAK/STAT were summarized under the background of CVDs. Finally, we discussed the clinical transformation prospects and toxicity of JAK/STAT inhibitors as potential therapeutic targets for CVDs. This collection of evidences has essential meanings for the clinical application of JAK/STAT as medicinal agents for CVDs.
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Affiliation(s)
- Qiuyu Pang
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lu You
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangmin Meng
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yumeng Li
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Deng
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Deyong Li
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Bingmei Zhu
- Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
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18
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Liu GY, Xie WL, Wang YT, Chen L, Xu ZZ, Lv Y, Wu QP. Calpain: the regulatory point of myocardial ischemia-reperfusion injury. Front Cardiovasc Med 2023; 10:1194402. [PMID: 37456811 PMCID: PMC10346867 DOI: 10.3389/fcvm.2023.1194402] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Calpain is a conserved cysteine protease readily expressed in several mammalian tissues, which is usually activated by Ca2+ and with maximum activity at neutral pH. The activity of calpain is tightly regulated because its aberrant activation will nonspecifically cleave various proteins in cells. Abnormally elevation of Ca2+ promotes the abnormal activation of calpain during myocardial ischemia-reperfusion, resulting in myocardial injury and cardiac dysfunction. In this paper, we mainly reviewed the effects of calpain in various programmed cell death (such as apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, and parthanatos) in myocardial ischemia-reperfusion. In addition, we also discussed the abnormal activation of calpain during myocardial ischemia-reperfusion, the effect of calpain on myocardial repair, and the possible future research directions of calpain.
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Affiliation(s)
- Guo-Yang Liu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Wan-Li Xie
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Yan-Ting Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Lu Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Zhen-Zhen Xu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Yong Lv
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Qing-Ping Wu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
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19
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Yang XM, Cohen MV, Sayner S, Audia JP, Downey JM. Lethal Caspase-1/4-Dependent Injury Occurs in the First Minutes of Coronary Reperfusion and Requires Calpain Activity. Int J Mol Sci 2023; 24:3801. [PMID: 36835212 PMCID: PMC9960231 DOI: 10.3390/ijms24043801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023] Open
Abstract
To study the relationship between caspase-1/4 and reperfusion injury, we measured infarct size (IS) in isolated mouse hearts undergoing 50 min global ischemia/2 h reperfusion. Starting VRT-043198 (VRT) at reperfusion halved IS. The pan-caspase inhibitor emricasan duplicated VRT's protection. IS in caspase-1/4-knockout hearts was similarly reduced, supporting the hypothesis that caspase-1/4 was VRT's only protective target. NLRC4 inflammasomes activate caspase-1. NLRC4 knockout hearts were not protected, eliminating NLRC4 as caspase-1/4's activator. The amount of protection that could be achieved by only suppressing caspase-1/4 activity was limited. In wild-type (WT) hearts, ischemic preconditioning (IPC) was as protective as caspase-1/4 inhibitors. Combining IPC and emricasan in these hearts or preconditioning caspase-1/4-knockout hearts produced an additive IS reduction, indicating that more protection could be achieved by combining treatments. We determined when caspase-1/4 exerted its lethal injury. Starting VRT after 10 min of reperfusion in WT hearts was no longer protective, revealing that caspase-1/4 inflicted its injury within the first 10 min of reperfusion. Ca++ influx at reperfusion might activate caspase-1/4. We tested whether Ca++-dependent soluble adenylyl cyclase (AC10) could be responsible. However, IS in AC10-/- hearts was not different from that in WT control hearts. Ca++-activated calpain has been implicated in reperfusion injury. Calpain could be releasing actin-bound procaspase-1 in cardiomyocytes, which would explain why caspase-1/4-related injury is confined to early reperfusion. The calpain inhibitor calpeptin duplicated emricasan's protection. Unlike IPC, adding calpain to emricasan offered no additional protection, suggesting that caspase-1/4 and calpain may share the same protective target.
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Affiliation(s)
- Xi-Ming Yang
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Michael V. Cohen
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
- Department of Medicine, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Sarah Sayner
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Jonathon P. Audia
- Department of Microbiology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - James M. Downey
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
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20
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Guan L, Yu Z, Che Z, Zhang H, Yu Y, Yang D, Qian D, Chen R, Yu M. Experimental diabetes exacerbates autophagic flux impairment during myocardial I/R injury through calpain-mediated cleavage of Atg5/LAMP2. J Cell Mol Med 2022; 27:232-245. [PMID: 36562207 PMCID: PMC9843523 DOI: 10.1111/jcmm.17642] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022] Open
Abstract
To explore the role of autophagic flux in the increased susceptibility of the experimental diabetic heart to ischaemia-reperfusion (I/R) injury, we established STZ-induced diabetic mice and performed I/R. In vitro, neonatal mouse cardiomyocytes were subjected to high glucose and hypoxia/reoxygenation challenge to mimic diabetic I/R injury. We found that experimental diabetes aggravated I/R-induced injury than compared with nondiabetic mice. Autophagic flux was impaired in I/R hearts, and the impairment was exacerbated in diabetic mice subjected to I/R with defective autophagosome formation and clearance. Calpains, calcium-dependent thiol proteases, were upregulated and highly activated after I/R of diabetes, while calpain inhibition attenuated cardiac function and cell death and partially restored autophagic flux. The expression levels of Atg5 and LAMP2, two crucial autophagy-related proteins, were significantly degraded in diabetic I/R hearts, alterations that were associated with calpain activation and could be reversed by calpain inhibition. Co-overexpression of Atg5 and LAMP2 reduced myocardial injury and normalized autophagic flux. In conclusion, experimental diabetes exacerbates autophagic flux impairment of cardiomyocytes under I/R stress, resulting in worse I/R-induced injury. Calpain activation and cleavage of Atg5 and LAMP2 at least partially account for the deterioration of autophagic flux impairment.
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Affiliation(s)
- Lichun Guan
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Ziqin Yu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Zhimei Che
- Department of Anesthesiology, Shanghai Chest HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Hang Zhang
- Department of Cardiovascular Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Yong Yu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Dicheng Yang
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Dewei Qian
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Ruizhen Chen
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Min Yu
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
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Khanahmad H, Mirbod SM, Karimi F, Kharazinejad E, Owjfard M, Najaflu M, Tavangar M. Pathological Mechanisms Induced by TRPM2 Ion Channels Activation in Renal Ischemia-Reperfusion Injury. Mol Biol Rep 2022; 49:11071-11079. [PMID: 36104583 DOI: 10.1007/s11033-022-07836-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/26/2022] [Accepted: 08/01/2022] [Indexed: 10/14/2022]
Abstract
Renal ischemia-reperfusion (IR) injury triggers a cascade of signaling reactions involving an increase in Ca2 + charge and reactive oxygen species (ROS) levels resulting in necrosis, inflammation, apoptosis, and subsequently acute kidney injury (AKI).Transient receptor potential (TRP) channels include an essential class of Ca2+ permeable cation channels, which are segregated into six main channels: the canonical channel (TRPC), the vanilloid-related channel (TRPV), the melastatin-related channel (TRPM), the ankyrin-related channel (TRPA), the mucolipin-related channel (TRPML) and polycystin-related channel (TRPP) or polycystic kidney disease protein (PKD2). TRP channels are involved in adjusting vascular tone, vascular permeability, cell volume, proliferation, secretion, angiogenesis and apoptosis.TRPM channels include eight isoforms (TRPM1-TRPM8) and TRPM2 is the second member of this subfamily that has been expressed in various tissues and organs such as the brain, heart, kidney and lung. Renal TRPM2 channels have an important role in renal IR damage. So that TRPM2 deficient mice are resistant to renal IR injury. TRPM2 channels are triggered by several chemicals including hydrogen peroxide, Ca2+, and cyclic adenosine diphosphate (ADP) ribose (cADPR) that are generated during AKI caused by IR injury, as well as being implicated in cell death caused by oxidative stress, inflammation, and apoptosis.
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Affiliation(s)
- Hossein Khanahmad
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of medical science, Isfahan, Iran
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical sciences, Isfahan, Iran, Isfahan University of Medical sciences, Isfahan, Iran
| | - Seyedeh Mahnaz Mirbod
- Resident of Cardiology, Department of cardiology, Isfahan University of Medical Science, Isfahan, Iran
- Department of Cardiology, Isfahan University of Medical Sciences, Isfahan, Iran., Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farzaneh Karimi
- Behbahan Faculty of Medical Sciences, Behbahan, Iran.
- Behbahan Faculty of Medical Sciences, No.8, Shahid Zibaei Blvd. Behbahan city, Behbahan, Khozestan province, Iran.
- Department of Physiology, Behbahan Faculty of Medical Sciences, Behbahan, Iran., Behbahan Faculty of Medical Sciences, Behbahan, Iran.
| | - Ebrahim Kharazinejad
- Abadan University of Medical Sciences, Abadan, Iran
- Department of Anatomy, Abadan University of Medical Sciences, Abadan, Iran, Abadan University of Medical Sciences, Abadan , Iran
| | - Maryam Owjfard
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Shiraz University of Applied Science and Technology (UAST), Shiraz, Iran
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Shiraz University of Applied Science and Technology (UAST), Shiraz, Iran, Shiraz University of Applied Science and Technology (UAST), Shiraz, Iran
| | - Malihe Najaflu
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrsa Tavangar
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran, Isfahan University of Medical Sciences, Isfahan, Iran
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22
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Benenati S, Crimi G, Macchione A, Giachero C, Pescetelli F, Balbi M, Porto I, Vercellino M. Mechanical Unloading of the Left Ventricle before Coronary Reperfusion in Preclinical Models of Myocardial Infarction without Cardiogenic Shock: A Meta-Analysis. J Clin Med 2022; 11:jcm11164913. [PMID: 36013152 PMCID: PMC9409839 DOI: 10.3390/jcm11164913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 12/09/2022] Open
Abstract
Aim: to compare a conventional primary reperfusion strategy with a primary unloading approach before reperfusion in preclinical studies. Methods: we performed a meta-analysis of preclinical studies. The primary endpoint was infarct size (IS). Secondary endpoints were left ventricle end-diastolic pressure (LVEDP), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO). We calculated mean differences (MDs) and associated 95% confidence intervals (CIs). Sensitivity and subgroup analyses on the primary and secondary endpoints, as well as a meta-regression on the primary endpoint using the year of publication as a covariate, were also conducted. Results: 11 studies (n = 142) were selected and entered in the meta-analysis. Primary unloading reduced IS (MD −28.82, 95% CI −35.78 to −21.86, I2 96%, p < 0.01) and LVEDP (MD −3.88, 95% CI −5.33 to −2.44, I2 56%, p = 0.02) and increased MAP (MD 7.26, 95% CI 1.40 to 13.12, I2 43%, p < 0.01) and HR (MD 5.26, 95% CI 1.97 to 8.55, I2 1%, p < 0.01), while being neutral on CO (MD −0.11, 95% CI −0.95 to 0.72, I2 88%, p = 0.79). Sensitivity and subgroup analyses showed, overall, consistent results. The meta-regression on the primary endpoint demonstrated a significant influence of the year of publication on effect estimate. Conclusions: in animal models of myocardial infarction, a primary unloading significantly reduces IS and exerts beneficial hemodynamic effects compared to a primary reperfusion.
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Affiliation(s)
- Stefano Benenati
- Cardiovascular Disease Chair, Department of Internal Medicine (Di.M.I.), University of Genoa, 16132 Genoa, Italy
| | - Gabriele Crimi
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, 16132 Genova, Italy
| | - Andrea Macchione
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, 16132 Genova, Italy
| | - Corinna Giachero
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, 16132 Genova, Italy
| | - Fabio Pescetelli
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, 16132 Genova, Italy
| | - Manrico Balbi
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, 16132 Genova, Italy
| | - Italo Porto
- Cardiovascular Disease Chair, Department of Internal Medicine (Di.M.I.), University of Genoa, 16132 Genoa, Italy
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, 16132 Genova, Italy
- Correspondence: ; Tel.: +39-0105555830
| | - Matteo Vercellino
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network, 16132 Genova, Italy
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23
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Ovchinnikov AN, Paoli A, Seleznev VV, Deryugina AV. Royal jelly plus coenzyme Q10 supplementation improves high-intensity interval exercise performance via changes in plasmatic and salivary biomarkers of oxidative stress and muscle damage in swimmers: a randomized, double-blind, placebo-controlled pilot trial. J Int Soc Sports Nutr 2022; 19:239-257. [PMID: 35813842 PMCID: PMC9261740 DOI: 10.1080/15502783.2022.2086015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Background Excessive production of free radicals caused by many types of exercise results in oxidative stress, which leads to muscle damage, fatigue, and impaired performance. Supplementation with royal jelly (RJ) or coenzyme Q10 (CoQ10) has been shown to attenuate exercise-induced oxidant stress in damaged muscle and improve various aspects of exercise performance in many but not all studies. Nevertheless, the effects of treatments based on RJ plus CoQ10 supplementation, which may be potentially beneficial for reducing oxidative stress and enhancing athletic performance, remain unexplored. This study aimed to examine whether oral RJ and CoQ10 co-supplementation could improve high-intensity interval exercise (HIIE) performance in swimmers, inhibiting exercise-induced oxidative stress and muscle damage. Methods Twenty high-level swimmers were randomly allocated to receive either 400 mg of RJ and 60 mg of CoQ10 (RJQ) or matching placebo (PLA) once daily for 10 days. Exercise performance was evaluated at baseline, and then reassessed at day 10 of intervention, using a HIIE protocol. Diene conjugates (DC), Schiff bases (SB), and creatine kinase (CK) were also measured in blood plasma and saliva before and immediately after HIIE in both groups. Results HIIE performance expressed as number of points according to a single assessment system developed and approved by the International Swimming Federation (FINA points) significantly improved in RJQ group (p = 0.013) compared to PLA group. Exercise-induced increase in DC, SB, and CK levels in plasma and saliva significantly diminished only in RJQ group (p < 0.05). Regression analysis showed that oral RJQ administration for 10 days was significantly associated with reductions in HIIE-induced increases in plasmatic and salivary DC, SB, and CK levels compared to PLA. Principal component analysis revealed that swimmers treated with RJQ are grouped by both plasmatic and salivary principal components (PC) into a separate cluster compared to PLA. Strong negative correlation between the number of FINA points and plasmatic and salivary PC1 values was observed in both intervention groups. Conclusion The improvements in swimmers’ HIIE performance were due in significant part to RJQ-induced reducing in lipid peroxidation and muscle damage in response to exercise. These findings suggest that RJQ supplementation for 10 days is potentially effective for enhancing HIIE performance and alleviating oxidant stress. Abbreviations RJ, royal jelly; CoQ10, coenzyme Q10; HIIE, high-intensity interval exercise; DC, diene conjugates; SB, Schiff bases; CK, creatine kinase; RJQ, royal jelly plus coenzyme Q10; PLA, placebo; FINA points, points according to a single assessment system developed and approved by the International Swimming Federation; ROS, reactive oxygen species; 10H2DA, 10-hydroxy-2-decenoic acid; AMPK, 5′-AMP-activated protein kinase; FoxO3, forkhead box O3; MnSOD, manganese-superoxide dismutase; CAT, catalase; E, optical densities; PCA, principal component analysis; PC, principal component; MCFAs, medium-chain fatty acids; CaMKKβ, Ca2+/calmodulin-dependent protein kinase β; TBARS, thiobarbituric acid reactive substances; MDA, malondialdehyde.
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Affiliation(s)
- Aleksandr N. Ovchinnikov
- Department of Sports Medicine and Psychology, Lobachevsky University, Nizhny Novgorod, Russia
- Laboratory of Integral Human Health, Lobachevsky University, Nizhny Novgorod, Russia
| | - Antonio Paoli
- Laboratory of Integral Human Health, Lobachevsky University, Nizhny Novgorod, Russia
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Vladislav V. Seleznev
- Department of Theory and Methodology of Sport Training, Lobachevsky University, Nizhny Novgorod, Russia
| | - Anna V. Deryugina
- Laboratory of Integral Human Health, Lobachevsky University, Nizhny Novgorod, Russia
- Department of Physiology and Anatomy, Lobachevsky University, Nizhny Novgorod, Russia
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24
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Ovchinnikov AN, Paoli A, Seleznev VV, Deryugina AV. Measurement of Lipid Peroxidation Products and Creatine Kinase in Blood Plasma and Saliva of Athletes at Rest and following Exercise. J Clin Med 2022; 11:jcm11113098. [PMID: 35683484 PMCID: PMC9181342 DOI: 10.3390/jcm11113098] [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: 04/23/2022] [Revised: 05/22/2022] [Accepted: 05/24/2022] [Indexed: 11/26/2022] Open
Abstract
This study aimed to assess the agreement between quantitative measurements of plasmatic and salivary biomarkers capable of identifying oxidative stress and muscle damage in athletes at rest and following exercise. Thirty-nine high-level athletes participating in track and field (running), swimming or rowing were recruited and assigned to one of three groups depending on the sport. Each athlete group underwent its specific exercise. Blood and saliva samples were collected before and immediately after the exercise. Diene conjugates (DC), triene conjugates (TC), Schiff bases (SB), and creatine kinase (CK) were measured. Comparisons were made using Wilcoxon signed-rank test. Correlation analysis and Bland−Altman method were applied. DC levels were elevated in plasma (p < 0.01) and saliva (p < 0.01) in response to exercise in all three groups, as were the plasmatic (p < 0.01) and salivary (p < 0.01) TC and SB concentrations. CK activity was also significantly higher at postexercise compared to pre-exercise in both plasma (p < 0.01) and saliva (p < 0.01) in all groups. Strong positive correlation between salivary and plasmatic DC (p < 0.001), TC (p < 0.001), SB (p < 0.01), and CK (p < 0.001) was observed at rest and following exercise in each athlete group. The bias calculated for DC, TC, SB, and CK using the Bland−Altman statistics was not significant at both pre-exercise and postexercise in all three groups. The line of equality was within the confidence interval of the mean difference. All of the data points lay within the respective agreement limits. Salivary concentrations of DC, TC, SB, and CK are able to reliably reflect their plasma levels.
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Affiliation(s)
- Aleksandr N. Ovchinnikov
- Department of Sports Medicine and Psychology, Lobachevsky University, 603022 Nizhny Novgorod, Russia
- Laboratory of Integral Human Health, Lobachevsky University, 603022 Nizhny Novgorod, Russia; (A.P.); (A.V.D.)
- Correspondence:
| | - Antonio Paoli
- Laboratory of Integral Human Health, Lobachevsky University, 603022 Nizhny Novgorod, Russia; (A.P.); (A.V.D.)
- Department of Biomedical Sciences, University of Padova, 35122 Padova, Italy
| | - Vladislav V. Seleznev
- Department of Theory and Methodology of Sport Training, Lobachevsky University, 603022 Nizhny Novgorod, Russia;
| | - Anna V. Deryugina
- Laboratory of Integral Human Health, Lobachevsky University, 603022 Nizhny Novgorod, Russia; (A.P.); (A.V.D.)
- Department of Physiology and Anatomy, Lobachevsky University, 603022 Nizhny Novgorod, Russia
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25
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Chen Q, Thompson J, Hu Y, Lesnefsky EJ. The mitochondrial electron transport chain contributes to calpain 1 activation during ischemia-reperfusion. Biochem Biophys Res Commun 2022; 613:127-132. [PMID: 35550199 DOI: 10.1016/j.bbrc.2022.04.117] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022]
Abstract
Activation of calpain1 (CPN1) contributes to mitochondrial dysfunction during cardiac ischemia (ISC) - reperfusion (REP). Blockade of electron transport using amobarbital (AMO) protects mitochondria during ISC-REP, indicating that the electron transport chain (ETC) is a key source of mitochondrial injury. We asked if AMO treatment can decrease CPN1 activation as a potential mechanism of mitochondrial protection during ISC-REP. Buffer-perfused adult rat hearts underwent 25 min global ISC and 30 min REP. AMO (2.5 mM) or vehicle was administered for 1 min before ISC to block electron flow in the ETC. Hearts in the time control group were untreated and buffer perfused without ISC. Hearts were collected at the end of perfusion and used for mitochondrial isolation. ISC-REP increased both the cleavage of spectrin (indicating cytosolic CPN1 activation) in cytosol and the truncation of AIF (apoptosis inducing factor, indicating mitochondrial CPN1 activation) in subsarcolemmal mitochondria compared to time control. Thus, ISC-REP activated both cytosolic and mitochondrial CPN1. AMO treatment prevented the cleavage of spectrin and AIF during ISC-REP, suggesting that the transient blockade of electron transport during ISC decreases CPN1 activation. AMO treatment decreased the activation of PARP [poly(ADP-ribose) polymerase] downstream of AIF that triggers caspase-independent apoptosis. AMO treatment also decreased the release of cytochrome c from mitochondria during ISC-REP that prevented caspase 3 activation. These results support that the damaged ETC activates CPN1 in cytosol and mitochondria during ISC-REP, likely via calcium overload and oxidative stress. Thus, AMO treatment to mitigate mitochondrial-driven cardiac injury can decrease both caspase-dependent and caspase-independent programmed cell death during ISC-REP.
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Affiliation(s)
- Qun Chen
- Departments of Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA, 23298, USA.
| | - Jeremy Thompson
- Departments of Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Ying Hu
- Departments of Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Edward J Lesnefsky
- Departments of Medicine (Division of Cardiology), Virginia Commonwealth University, Richmond, VA, 23298, USA; Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, 23298, USA; Departments of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, 23298, USA; Richmond Department of Veterans Affairs Medical Center, Richmond, VA, 23249, USA
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26
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Aluja D, Delgado-Tomás S, Ruiz-Meana M, Barrabés JA, Inserte J. Calpains as Potential Therapeutic Targets for Myocardial Hypertrophy. Int J Mol Sci 2022; 23:ijms23084103. [PMID: 35456920 PMCID: PMC9032729 DOI: 10.3390/ijms23084103] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/26/2022] [Accepted: 04/06/2022] [Indexed: 11/25/2022] Open
Abstract
Despite advances in its treatment, heart failure remains a major cause of morbidity and mortality, evidencing an urgent need for novel mechanism-based targets and strategies. Myocardial hypertrophy, caused by a wide variety of chronic stress stimuli, represents an independent risk factor for the development of heart failure, and its prevention constitutes a clinical objective. Recent studies performed in preclinical animal models support the contribution of the Ca2+-dependent cysteine proteases calpains in regulating the hypertrophic process and highlight the feasibility of their long-term inhibition as a pharmacological strategy. In this review, we discuss the existing evidence implicating calpains in the development of cardiac hypertrophy, as well as the latest advances in unraveling the underlying mechanisms. Finally, we provide an updated overview of calpain inhibitors that have been explored in preclinical models of cardiac hypertrophy and the progress made in developing new compounds that may serve for testing the efficacy of calpain inhibition in the treatment of pathological cardiac hypertrophy.
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Affiliation(s)
- David Aluja
- Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; (D.A.); (S.D.-T.); (M.R.-M.); (J.A.B.)
| | - Sara Delgado-Tomás
- Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; (D.A.); (S.D.-T.); (M.R.-M.); (J.A.B.)
| | - Marisol Ruiz-Meana
- Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; (D.A.); (S.D.-T.); (M.R.-M.); (J.A.B.)
- Centro de Investigación en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - José A. Barrabés
- Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; (D.A.); (S.D.-T.); (M.R.-M.); (J.A.B.)
- Centro de Investigación en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
| | - Javier Inserte
- Cardiovascular Diseases Research Group, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain; (D.A.); (S.D.-T.); (M.R.-M.); (J.A.B.)
- Centro de Investigación en Red de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-934894038
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27
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Li L, Thompson J, Hu Y, Lesnefsky EJ, Willard B, Chen Q. Calpain-mediated protein targets in cardiac mitochondria following ischemia-reperfusion. Sci Rep 2022; 12:138. [PMID: 34997008 PMCID: PMC8741987 DOI: 10.1038/s41598-021-03947-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 12/09/2021] [Indexed: 12/30/2022] Open
Abstract
Calpain 1 and 2 (CPN1/2) are calcium-dependent cysteine proteases that exist in cytosol and mitochondria. Pharmacologic inhibition of CPN1/2 decreases cardiac injury during ischemia (ISC)-reperfusion (REP) by improving mitochondrial function. However, the protein targets of CPN1/2 activation during ISC-REP are unclear. CPN1/2 include a large subunit and a small regulatory subunit 1 (CPNS1). Genetic deletion of CPNS1 eliminates the activities of both CPN1 and CPN2. Conditional cardiomyocyte specific CPNS1 deletion mice were used in the present study to clarify the role of CPN1/2 activation in mitochondrial damage during ISC-REP with an emphasis on identifying the potential protein targets of CPN1/2. Isolated hearts from wild type (WT) or CPNS1 deletion mice underwent 25 min in vitro global ISC and 30 min REP. Deletion of CPNS1 led to decreased cytosolic and mitochondrial calpain 1 activation compared to WT. Cardiac injury was decreased in CPNS1 deletion mice following ISC-REP as shown by the decreased infarct size compared to WT. Compared to WT, mitochondrial function was improved in CPNS1 deletion mice following ischemia-reperfusion as shown by the improved oxidative phosphorylation and decreased susceptibility to mitochondrial permeability transition pore opening. H2O2 generation was also decreased in mitochondria from deletion mice following ISC-REP compared to WT. Deletion of CPNS1 also resulted in less cytochrome c and truncated apoptosis inducing factor (tAIF) release from mitochondria. Proteomic analysis of the isolated mitochondria showed that deletion of CPNS1 increased the content of proteins functioning in regulation of mitochondrial calcium homeostasis (paraplegin and sarcalumenin) and complex III activity. These results suggest that activation of CPN1 increases cardiac injury during ischemia-reperfusion by impairing mitochondrial function and triggering cytochrome c and tAIF release from mitochondria into cytosol.
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Affiliation(s)
- Ling Li
- Proteomics Core, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Jeremy Thompson
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Ying Hu
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA
| | - Edward J Lesnefsky
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, 23298, USA
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, 23298, USA
- McGuire Department of Veterans Affairs Medical Center, Richmond, VA, 23249, USA
| | - Belinda Willard
- Proteomics Core, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Qun Chen
- Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
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28
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Gu QL, Jiang P, Ruan HF, Tang H, Liang YB, Ma ZF, Zhan H. The expression of oxidative stress genes related to myocardial ischemia reperfusion injury in patients with ST-elevation myocardial infarction. World J Emerg Med 2022; 13:106-113. [PMID: 35237363 PMCID: PMC8861342 DOI: 10.5847/wjem.j.1920-8642.2022.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 12/20/2020] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND We aimed to investigate the gene expression of myocardial ischemia/reperfusion injury (MIRI) in patients with acute ST-elevation myocardial infarction (STEMI) using stress and toxicity pathway gene chip technology and try to determine the underlying mechanism. METHODS The mononuclear cells were separated by ficoll centrifugation, and plasma total antioxidant capacity (T-AOC) was determined by the ferric reducing ability of plasma (FRAP) assay. The expression of toxic oxidative stress genes was determined and verified by oligo gene chip and quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, gene ontology (GO) enrichment analysis was performed on DAVID website to analyze the potential mechanism further. RESULTS The total numbers of white blood cells (WBC) and neutrophils (N) in the peripheral blood of STEMI patients (the AMI group) were significantly higher than those in the control group (WBC: 11.67±4.85 ×109/L vs. 6.41±0.72 ×109/L, P<0.05; N: 9.27±4.75 ×109/L vs. 3.89±0.81 ×109/L, P<0.05), and WBCs were significantly associated with creatine kinase-myocardial band (CK-MB) on the first day (Y=8.945+0.018X, P<0.05). In addition, the T-AOC was significantly lower in the AMI group comparing to the control group (12.80±1.79 U/mL vs. 20.48±2.55 U/mL, P<0.05). According to the gene analysis, eight up-regulated differentially expressed genes (DEGs) included GADD45A, PRDX2, HSPD1, DNAJB1, DNAJB2, RAD50, TNFSF6, and TRADD. Four down-regulated DEGs contained CCNG1, CAT, CYP1A1, and ATM. TNFSF6 and CYP1A1 were detected by polymerase chain reaction (PCR) to verify the expression at different time points, and the results showed that TNFSF6 was up-regulated and CYP1A1 was down-regulated as the total expression. GO and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the oxidative stress genes mediate MIRI via various ways such as unfolded protein response (UPR) and apoptosis. CONCLUSIONS WBCs, especially neutrophils, were the critical cells that mediating reperfusion injury. MIRI was regulated by various genes, including oxidative metabolic stress, heat shock, DNA damage and repair, and apoptosis-related genes. The underlying pathway may be associated with UPR and apoptosis, which may be the novel therapeutic target.
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Affiliation(s)
- Qian-lin Gu
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Peng Jiang
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Hui-fen Ruan
- Huangpu District Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Hao Tang
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Yang-bing Liang
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Zhong-fu Ma
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
| | - Hong Zhan
- Emergency Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510000, China
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29
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Ottolia M, John S, Hazan A, Goldhaber JI. The Cardiac Na + -Ca 2+ Exchanger: From Structure to Function. Compr Physiol 2021; 12:2681-2717. [PMID: 34964124 DOI: 10.1002/cphy.c200031] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Ca2+ homeostasis is essential for cell function and survival. As such, the cytosolic Ca2+ concentration is tightly controlled by a wide number of specialized Ca2+ handling proteins. One among them is the Na+ -Ca2+ exchanger (NCX), a ubiquitous plasma membrane transporter that exploits the electrochemical gradient of Na+ to drive Ca2+ out of the cell, against its concentration gradient. In this critical role, this secondary transporter guides vital physiological processes such as Ca2+ homeostasis, muscle contraction, bone formation, and memory to name a few. Herein, we review the progress made in recent years about the structure of the mammalian NCX and how it relates to function. Particular emphasis will be given to the mammalian cardiac isoform, NCX1.1, due to the extensive studies conducted on this protein. Given the degree of conservation among the eukaryotic exchangers, the information highlighted herein will provide a foundation for our understanding of this transporter family. We will discuss gene structure, alternative splicing, topology, regulatory mechanisms, and NCX's functional role on cardiac physiology. Throughout this article, we will attempt to highlight important milestones in the field and controversial topics where future studies are required. © 2021 American Physiological Society. Compr Physiol 12:1-37, 2021.
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Affiliation(s)
- Michela Ottolia
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Scott John
- Department of Medicine (Cardiology), UCLA, Los Angeles, California, USA
| | - Adina Hazan
- Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Joshua I Goldhaber
- Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California, USA
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30
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Zhang K, Cremers MM, Wiedemann S, Poitz DM, Pfluecke C, Heinzel FR, Pieske B, Adams V, Schauer A, Winzer R, Strasser RH, Linke A, Quick S, Heidrich FM. Spatio-temporal regulation of calpain activity after experimental myocardial infarction in vivo. Biochem Biophys Rep 2021; 28:101162. [PMID: 34761128 PMCID: PMC8566776 DOI: 10.1016/j.bbrep.2021.101162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/25/2021] [Accepted: 10/25/2021] [Indexed: 11/30/2022] Open
Abstract
Background Calpains are calcium activated cysteine proteases that play a pivotal role in the pathophysiology of cardiac remodeling. Methods Here, we performed left anterior descending coronary artery ligation in rats as a model for ischemic systolic heart failure and examined the time- and region-specific regulation of calpain-1 and calpain-2 in the left ventricular myocardium. Results Following anterior wall myocardial infarction, calpain activity was significantly increased restricted to the ischemic anterior area at days 1, 5 and 14. No changes in calpain activity at neither time point were detected in the borderzone and remote posterior area of the left ventricle. Of note, calpain activity in the infarcted anterior myocardium was regulated differentially in the acute vs. subacute and chronic phase. In the acute phase, calpain translocation to the plasma membrane and attenuation of the expression of its endogenous inhibitor, calpastatin, were identified as the driving forces. In the subacute and chronic phase, calpain activity was regulated at the level of protein expression that was shown to be essentially independent of transcriptional activity. Conclusions We conclude that myocardial infarction leads to a distinct calpain regulation pattern in the left ventricular myocardium that is region specific and time dependent. Considering the results from our previous studies, a spatio-temporal interaction between calpains and calcium dependent natriuretic peptide production in the infarcted myocardium is possible. General significance Our results shed more light in the differential regulation of calpain activity in the myocardium and might aid in the development of targeted post-infarct and/or heart failure therapeutics.
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Key Words
- AGTR1, angiotensin II receptor type 1
- Calcium
- Calpain
- Calpain-1
- Calpain-2
- Calpastatin
- Experimental myocardial infarction
- InsP3, inositol 1,4,5-trisphosphate
- InsP3R, inositol 1,4,5-trisphopshate receptor
- LAD, left anterior descending
- LVEDD, left ventricular enddiastolic diameter
- LVEF, left ventricular ejection fraction
- LVESD, left ventricular endsystolic diameter
- NF-ĸB, nuclear factor kappa B
- NT pro-ANP, N-terminal pro atrial natriuretic peptide
- SBDP, spectrin breakdown products
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Affiliation(s)
- Kun Zhang
- Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Melissa M Cremers
- Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universität Dresden, Dresden, Germany
| | - Stephan Wiedemann
- Helios Klinikum Pirna, Department of Internal Medicine and Cardiology, Pirna, Germany
| | - David M Poitz
- Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
| | - Christian Pfluecke
- Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universität Dresden, Dresden, Germany
| | - Frank R Heinzel
- Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Burkert Pieske
- Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.,Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany
| | - Volker Adams
- Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universität Dresden, Dresden, Germany
| | - Antje Schauer
- Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universität Dresden, Dresden, Germany
| | - Robert Winzer
- Institute and Policlinic for Diagnostic and Interventional Radiology, University Hospital, Carl Gustav Carus University, Technische Universität Dresden, Dresden, Germany
| | - Ruth H Strasser
- Technische Universität Dresden, Medical Faculty, Dresden, Germany
| | - Axel Linke
- Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universität Dresden, Dresden, Germany
| | - Silvio Quick
- Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universität Dresden, Dresden, Germany
| | - Felix M Heidrich
- Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universität Dresden, Dresden, Germany
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Mauerhofer C, Grumet L, Schemmer P, Leber B, Stiegler P. Combating Ischemia-Reperfusion Injury with Micronutrients and Natural Compounds during Solid Organ Transplantation: Data of Clinical Trials and Lessons of Preclinical Findings. Int J Mol Sci 2021; 22:10675. [PMID: 34639016 PMCID: PMC8508760 DOI: 10.3390/ijms221910675] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/22/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
Although extended donor criteria grafts bear a higher risk of complications such as graft dysfunction, the exceeding demand requires to extent the pool of potential donors. The risk of complications is highly associated with ischemia-reperfusion injury, a condition characterized by high loads of oxidative stress exceeding antioxidative defense mechanisms. The antioxidative properties, along with other beneficial effects like anti-inflammatory, antiapoptotic or antiarrhythmic effects of several micronutrients and natural compounds, have recently emerged increasing research interest resulting in various preclinical and clinical studies. Preclinical studies reported about ameliorated oxidative stress and inflammatory status, resulting in improved graft survival. Although the majority of clinical studies confirmed these results, reporting about improved recovery and superior organ function, others failed to do so. Yet, only a limited number of micronutrients and natural compounds have been investigated in a (large) clinical trial. Despite some ambiguous clinical results and modest clinical data availability, the vast majority of convincing animal and in vitro data, along with low cost and easy availability, encourage the conductance of future clinical trials. These should implement insights gained from animal data.
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Affiliation(s)
- Christina Mauerhofer
- Department of Science and Product Development, pro medico HandelsGmbH, Liebenauer Tangente 6, 8041 Graz, Austria; (C.M.); (L.G.)
| | - Lukas Grumet
- Department of Science and Product Development, pro medico HandelsGmbH, Liebenauer Tangente 6, 8041 Graz, Austria; (C.M.); (L.G.)
| | - Peter Schemmer
- Division of Transplant Surgery, Department of Surgery, Medical University, 8036 Graz, Austria; (P.S.); (B.L.)
| | - Bettina Leber
- Division of Transplant Surgery, Department of Surgery, Medical University, 8036 Graz, Austria; (P.S.); (B.L.)
| | - Philipp Stiegler
- Division of Transplant Surgery, Department of Surgery, Medical University, 8036 Graz, Austria; (P.S.); (B.L.)
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32
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Dynamic Regulation of Cysteine Oxidation and Phosphorylation in Myocardial Ischemia-Reperfusion Injury. Cells 2021; 10:cells10092388. [PMID: 34572037 PMCID: PMC8469016 DOI: 10.3390/cells10092388] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 02/02/2023] Open
Abstract
Myocardial ischemia-reperfusion (I/R) injury significantly alters heart function following infarct and increases the risk of heart failure. Many studies have sought to preserve irreplaceable myocardium, termed cardioprotection, but few, if any, treatments have yielded a substantial reduction in clinical I/R injury. More research is needed to fully understand the molecular pathways that govern cardioprotection. Redox mechanisms, specifically cysteine oxidations, are acute and key regulators of molecular signaling cascades mediated by kinases. Here, we review the role of reactive oxygen species in modifying cysteine residues and how these modifications affect kinase function to impact cardioprotection. This exciting area of research may provide novel insight into mechanisms and likely lead to new treatments for I/R injury.
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Abstract
Despite the progress of cardiovascular medicine, ischemia-reperfusion injury can contribute to increased mortality and prolonged hospitalization after myocardial infarction. Ischemia-reperfusion injury pathophysiology encompasses many cells including cardiomyocytes, fibroblasts, mesenchymal stromal cells, vascular endothelial and smooth muscle cells, platelets, polymorphonuclear cells, macrophages, and T lymphocytes. However, specific mechanisms for all contributing cells and molecular pathways are still under investigation. What is definitely known is that endothelial dysfunction, immunity activation and inflammatory response are crucial events during ischemia-reperfusion injury while toll-like receptors, inflammasomes, reactive oxygen species, intracellular calcium overload and mitochondrial permeability transition pore opening consist of key molecular mediators. Indicatively, cardiac fibroblasts through inflammasome activation mediate the initial inflammatory response. Cardiac mesenchymal stromal cells can respond to myocardial injury by pro-inflammatory activation. Endothelial cell activation contributes to the impaired vasomotion, inflammation and thrombotic events and together with platelet activation leads to microcirculation dysfunction and polymorphonuclear cells recruitment promoting inflammation. Polymorphonuclear cells and monocytes/macrophages subsets are critically involved in the inflammation process by producing toxic proteolytic enzymes and reactive oxygen species. T cells subsets are also involved in several stages of ischemia-reperfusion injury. In this review, we summarize the specific contribution of each of the above cells and the related molecular pathways in the pathophysiology of ischemia-reperfusion injury.
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Affiliation(s)
| | | | - Dimitrios Stakos
- Cardiology Department, Democritus University of Thrace, Alexandroupolis, Greece
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34
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Wang L, Li Q, Diao J, Lin L, Wei J. MiR-23a Is Involved in Myocardial Ischemia/Reperfusion Injury by Directly Targeting CX43 and Regulating Mitophagy. Inflammation 2021; 44:1581-1591. [PMID: 33651309 DOI: 10.1007/s10753-021-01443-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/19/2021] [Accepted: 02/22/2021] [Indexed: 01/20/2023]
Abstract
Activation of CX43 signaling protects myocardial cells from myocardial ischemia/reperfusion (I/R) injury. However, the underlying mechanism remains unclear. MicroRNAs (miRNAs) are well known to play important roles in the progression of diverse diseases. Here, we first confirmed the expression profile of CX43 in rat heart tissues with I/R injury. Then, microRNAs (miRNAs) that target CX43 were predicted using miRDB, miRWalk, and TargetScan. The candidate miR-23a was selected, and its expression level in I/R samples was investigated. To determine the role of miR-23a, rat primary myocardial cells were transfected with miR-23a mimics after they were subjected to hypoxia-reoxygenation (H/R) injury. Transfection of miR-23a mimics stimulated mitophagy through the PINK1/Parkin pathway and downregulated the protein level of CX43. Treatment of miR-23a-transfected cells with NF-kB inhibitors completely abolished miR-23a-mediated mitophagy after H/R. Moreover, miR-23a transfection significantly suppressed CX43 expression and enhanced mitophagy in the model heart in vivo. Therefore, miR-23a plays a detrimental role in myocardial I/R injury by enhancing mitophagy and inhibiting CX43 mRNA.
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Affiliation(s)
- Lina Wang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China
| | - Qing Li
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jiayu Diao
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China
| | - Lin Lin
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China
| | - Jin Wei
- Department of Cardiovascular Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
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35
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Chelko SP, Keceli G, Carpi A, Doti N, Agrimi J, Asimaki A, Beti CB, Miyamoto M, Amat-Codina N, Bedja D, Wei AC, Murray B, Tichnell C, Kwon C, Calkins H, James CA, O'Rourke B, Halushka MK, Melloni E, Saffitz JE, Judge DP, Ruvo M, Kitsis RN, Andersen P, Di Lisa F, Paolocci N. Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy. Sci Transl Med 2021; 13:13/581/eabf0891. [PMID: 33597260 DOI: 10.1126/scitranslmed.abf0891] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 01/27/2021] [Indexed: 12/15/2022]
Abstract
Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2 mut/mut), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2 mut/mut hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2 mut/mut mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca2+ overload-induced necrosis. When cardiomyocytes differentiated from Dsg2 mut/mut embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2 mut/mut ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.
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Affiliation(s)
- Stephen P Chelko
- Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306, USA. .,Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Gizem Keceli
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Andrea Carpi
- Department of Biomedical Sciences, University of Padova, Padova 35122, Italy
| | - Nunzianna Doti
- Institute of Biostructures and Bioimaging, CNR, Naples 80134, Italy
| | - Jacopo Agrimi
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Angeliki Asimaki
- Molecular and Clinical Sciences Research Institute, St. George's, University of London, London WC1E 6BS, UK
| | - Carlos Bueno Beti
- Molecular and Clinical Sciences Research Institute, St. George's, University of London, London WC1E 6BS, UK
| | - Matthew Miyamoto
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Nuria Amat-Codina
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Djahida Bedja
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.,Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia
| | - An-Chi Wei
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Brittney Murray
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Crystal Tichnell
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Chulan Kwon
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Hugh Calkins
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Cynthia A James
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Brian O'Rourke
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Marc K Halushka
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Edon Melloni
- Department of Medicine, University of Genova, Genova 16126, Italy
| | - Jeffrey E Saffitz
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 20115, USA
| | - Daniel P Judge
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.,Medical University of South Carolina, Charleston, SC 29425, USA
| | - Menotti Ruvo
- Institute of Biostructures and Bioimaging, CNR, Naples 80134, Italy
| | - Richard N Kitsis
- Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Peter Andersen
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Fabio Di Lisa
- Department of Biomedical Sciences, University of Padova, Padova 35122, Italy
| | - Nazareno Paolocci
- Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. .,Department of Biomedical Sciences, University of Padova, Padova 35122, Italy
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36
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Bandaru S, Ala C, Zhou AX, Akyürek LM. Filamin A Regulates Cardiovascular Remodeling. Int J Mol Sci 2021; 22:ijms22126555. [PMID: 34207234 PMCID: PMC8235345 DOI: 10.3390/ijms22126555] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 01/25/2023] Open
Abstract
Filamin A (FLNA) is a large actin-binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C-terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells. Localized FLNA mutations associate with cardiovascular malformations in humans. A lack of FLNA in experimental animal models disrupts cell migration during embryogenesis and causes anomalies, including heart and vessels, similar to human malformations. More recently, it was shown that FLNA mediates the progression of myocardial infarction and atherosclerosis. Thus, these latest findings identify FLNA as an important novel mediator of cardiovascular development and remodeling, and thus a potential target for therapy. In this update, we summarized the literature on filamin biology with regard to cardiovascular cell function.
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Affiliation(s)
- Sashidar Bandaru
- Division of Clinical Pathology, Sahlgrenska Academy Hospital, 413 45 Gothenburg, Sweden;
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; (C.A.); (A.-X.Z.)
| | - Chandu Ala
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; (C.A.); (A.-X.Z.)
| | - Alex-Xianghua Zhou
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; (C.A.); (A.-X.Z.)
| | - Levent M. Akyürek
- Division of Clinical Pathology, Sahlgrenska Academy Hospital, 413 45 Gothenburg, Sweden;
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; (C.A.); (A.-X.Z.)
- Correspondence:
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37
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Querio G, Geddo F, Antoniotti S, Gallo MP, Penna C. Sex and Response to Cardioprotective Conditioning Maneuvers. Front Physiol 2021; 12:667961. [PMID: 34054579 PMCID: PMC8160310 DOI: 10.3389/fphys.2021.667961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 03/30/2021] [Indexed: 12/02/2022] Open
Abstract
Ischemic heart disease (IHD) is a multifactorial pathological condition strictly related to genetic, dietary, and lifestyle factors. Its morbidity and mortality rate represent one of the most important pathological issues that today involve younger people in a stronger way than in the past. IHD clinical outcomes are difficult to treat and have a high economic impact on health care. So prevention of this pathological condition through cardioprotective maneuvers represents the first line of intervention, as already underlined by several animal and human studies. Even if the time of intervention is important to prevent severe outcomes, many studies highlight that sex-dependent responses are crucial for the result of cardioprotective procedures. In this scenario sexual hormones have revealed an important role in cardioprotective approach, as women seem to be more protected toward cardiac insults when compared to male counterparts. The aim of this mini review is to show the molecular pathways involved in cardioprotective protocols and to elucidate how sexual hormones can contribute in ameliorating or worsening the physiological responses to IHD.
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Affiliation(s)
- Giulia Querio
- Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy
| | - Federica Geddo
- Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy
| | - Susanna Antoniotti
- Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy
| | - Maria Pia Gallo
- Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy
| | - Claudia Penna
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
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38
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Cullen PP, Tsui SS, Caplice NM, Hinchion JA. A state-of-the-art review of the current role of cardioprotective techniques in cardiac transplantation. Interact Cardiovasc Thorac Surg 2021; 32:683-694. [PMID: 33971665 DOI: 10.1093/icvts/ivaa333] [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: 09/28/2020] [Revised: 11/24/2020] [Accepted: 12/06/2020] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES The use of 'extended criteria' donor hearts and reconditioned hearts from donation after circulatory death has corresponded with an increase in primary graft dysfunction, with ischaemia-reperfusion injury being a major contributing factor in its pathogenesis. Limiting ischaemia-reperfusion injury through optimising donor heart preservation may significantly improve outcomes. We sought to review the literature to evaluate the evidence for this. METHODS A review of the published literature was performed to assess the potential impact of organ preservation optimisation on cardiac transplantation outcomes. RESULTS Ischaemia-reperfusion injury is a major factor in myocardial injury during transplantation with multiple potential therapeutic targets. Innate survival pathways have been identified, which can be mimicked with pharmacological conditioning. Although incompletely understood, discoveries in this domain have yielded extremely encouraging results with one of the most exciting prospects being the synergistic effect of selected agents. Ex situ heart perfusion is an additional promising adjunct. CONCLUSIONS Cardiac transplantation presents a unique opportunity to perfuse the whole heart before, or immediately after, the onset of ischaemia, thus maximising the potential for global cardioprotection while limiting possible systemic side effects. While clinical translation in the setting of myocardial infarction has often been disappointing, cardiac transplantation may afford the opportunity for cardioprotection to finally deliver on its preclinical promise.
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Affiliation(s)
- Paul P Cullen
- Department of Cardiothoracic Surgery, Cork University Hospital, Cork, Ireland
| | - Steven S Tsui
- Department of Transplantation, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK
| | - Noel M Caplice
- Centre for Research in Vascular Biology, Biosciences Institute, University College Cork, Cork, Ireland
| | - John A Hinchion
- Department of Cardiothoracic Surgery, Cork University Hospital, Cork, Ireland
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39
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Bou-Teen D, Kaludercic N, Weissman D, Turan B, Maack C, Di Lisa F, Ruiz-Meana M. Mitochondrial ROS and mitochondria-targeted antioxidants in the aged heart. Free Radic Biol Med 2021; 167:109-124. [PMID: 33716106 DOI: 10.1016/j.freeradbiomed.2021.02.043] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/14/2021] [Accepted: 02/26/2021] [Indexed: 12/12/2022]
Abstract
Excessive mitochondrial ROS production has been causally linked to the pathophysiology of aging in the heart and other organs, and plays a deleterious role in several age-related cardiac pathologies, including myocardial ischemia-reperfusion injury and heart failure, the two worldwide leading causes of death and disability in the elderly. However, ROS generation is also a fundamental mitochondrial function that orchestrates several signaling pathways, some of them exerting cardioprotective effects. In cardiac myocytes, mitochondria are particularly abundant and are specialized in subcellular populations, in part determined by their relationships with other organelles and their cyclic calcium handling activity necessary for adequate myocardial contraction/relaxation and redox balance. Depending on their subcellular location, mitochondria can themselves be differentially targeted by ROS and display distinct age-dependent functional decline. Thus, precise mitochondria-targeted therapies aimed at counteracting unregulated ROS production are expected to have therapeutic benefits in certain aging-related heart conditions. However, for an adequate design of such therapies, it is necessary to unravel the complex and dynamic interactions between mitochondria and other cellular processes.
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Affiliation(s)
- Diana Bou-Teen
- Hospital Universitari Vall d'Hebron, Department of Cardiology, Vall d'Hebron Institut de Recerca (VHIR),Universitat Autonoma de Barcelona, 08035, Barcelona, Spain
| | - Nina Kaludercic
- Neuroscience Institute, National Research Council of Italy (CNR), via Ugo Bassi 58/B, 35131, Padova, Italy; Fondazione Istituto di Ricerca Pediatrica Città della Speranza (IRP), 35129, Padova, Italy
| | - David Weissman
- Comprehensive Heart Failure Center, University Clinic Würzburg, 97080, Würzburg, Germany
| | - Belma Turan
- Departments of Biophysics, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey
| | - Christoph Maack
- Comprehensive Heart Failure Center, University Clinic Würzburg, 97080, Würzburg, Germany
| | - Fabio Di Lisa
- Neuroscience Institute, National Research Council of Italy (CNR), via Ugo Bassi 58/B, 35131, Padova, Italy; Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35131, Padova, Italy
| | - Marisol Ruiz-Meana
- Hospital Universitari Vall d'Hebron, Department of Cardiology, Vall d'Hebron Institut de Recerca (VHIR),Universitat Autonoma de Barcelona, 08035, Barcelona, Spain; Centro de Investigación Biomédica en Red-CV, CIBER-CV, Spain.
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40
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Abstract
Unlike acute myocardial infarction with reperfusion, in which infarct size is the end point reflecting irreversible injury, myocardial stunning and hibernation result from reversible myocardial ischaemia-reperfusion injury, and contractile dysfunction is the obvious end point. Stunned myocardium is characterized by a disproportionately long-lasting, yet fully reversible, contractile dysfunction that follows brief bouts of myocardial ischaemia. Reperfusion precipitates a burst of reactive oxygen species formation and alterations in excitation-contraction coupling, which interact and cause the contractile dysfunction. Hibernating myocardium is characterized by reduced regional contractile function and blood flow, which both recover after reperfusion or revascularization. Short-term myocardial hibernation is an adaptation of contractile function to the reduced blood flow such that energy and substrate metabolism recover during the ongoing ischaemia. Chronic myocardial hibernation is characterized by severe morphological alterations and altered expression of metabolic and pro-survival proteins. Myocardial stunning is observed clinically and must be recognized but is rarely haemodynamically compromising and does not require treatment. Myocardial hibernation is clinically identified with the use of imaging techniques, and the myocardium recovers after revascularization. Several trials in the past two decades have challenged the superiority of revascularization over medical therapy for symptomatic relief and prognosis in patients with chronic coronary syndromes. A better understanding of the pathophysiology of myocardial stunning and hibernation is important for a more precise indication of revascularization and its consequences. Therefore, this Review summarizes the current knowledge of the pathophysiology of these characteristic reperfusion phenomena and highlights their clinical implications.
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41
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Ruan Y, Zeng J, Jin Q, Chu M, Ji K, Wang Z, Li L. Endoplasmic reticulum stress serves an important role in cardiac ischemia/reperfusion injury (Review). Exp Ther Med 2020; 20:268. [PMID: 33199993 PMCID: PMC7664614 DOI: 10.3892/etm.2020.9398] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/19/2020] [Indexed: 12/12/2022] Open
Abstract
Although acute myocardial infarction is one of the most common fatal diseases worldwide, the understanding of its underlying pathogenesis continues to develop. Myocardial ischemia/reperfusion (I/R) can restore myocardial oxygen and nutrient supply. However, a large number of studies have demonstrated that recovery of blood perfusion after acute ischemia causes reperfusion injury to the heart. With progress made in the understanding of the underlying mechanisms of myocardial I/R and oxidative stress, a novel area of research that merits greater study has been identified, that of I/R-induced endoplasmic reticulum (ER) stress (ERS). Cardiac I/R can alter the function of the ER, leading to the accumulation of unfolded/misfolded proteins. The resulting ERS then induces the activation of signal transduction pathways, which in turn contribute to the development of I/R injury. The mechanism of I/R injury, and the causal relationship between I/R and ERS are reviewed in the present article.
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Affiliation(s)
- Yongxue Ruan
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Jingjing Zeng
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Qike Jin
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Maoping Chu
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Kangting Ji
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Zhongyu Wang
- Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Lei Li
- Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
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Zhang J, Ren D, Fedorova J, He Z, Li J. SIRT1/SIRT3 Modulates Redox Homeostasis during Ischemia/Reperfusion in the Aging Heart. Antioxidants (Basel) 2020; 9:antiox9090858. [PMID: 32933202 PMCID: PMC7556005 DOI: 10.3390/antiox9090858] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/08/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022] Open
Abstract
Ischemia/reperfusion (I/R) injury is the central cause of global death in cardiovascular diseases, which is characterized by disorders such as angina, stroke, and peripheral vascular disease, finally causing severe debilitating diseases and death. The increased rates of morbidity and mortality caused by I/R are parallel with aging. Aging-associated cardiac physiological structural and functional deterioration were found to contribute to abnormal reactive oxygen species (ROS) production during I/R stress. Disturbed redox homeostasis could further trigger the related signaling pathways that lead to cardiac irreversible damages with mitochondria dysfunction and cell death. It is notable that sirtuin proteins are impaired in aged hearts and are critical to maintaining redox homeostasis via regulating substrate metabolism and inflammation and thus preserving cardiac function under stress. This review discussed the cellular and functional alterations upon I/R especially in aging hearts. We propose that mitochondria are the primary source of reactive oxygen species (ROS) that contribute to I/R injury in aged hearts. Then, we highlight the cardiomyocyte protection of the age-related proteins Sirtuin1 (SIRT1) and Sirtuin1 (SIRT3) in response to I/R injury, and we discuss their modulation of cardiac metabolism and the inflammatory reaction that is involved in ROS formation.
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Affiliation(s)
- Jingwen Zhang
- College of Life Sciences, Shandong Normal University, Jinan 250014, China;
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (D.R.); (J.F.); (Z.H.)
| | - Di Ren
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (D.R.); (J.F.); (Z.H.)
| | - Julia Fedorova
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (D.R.); (J.F.); (Z.H.)
| | - Zhibin He
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (D.R.); (J.F.); (Z.H.)
| | - Ji Li
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (D.R.); (J.F.); (Z.H.)
- Correspondence: ; Tel.: +1-813-974-4917
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Zhang C, He M, Ni L, He K, Su K, Deng Y, Li Y, Xia H. The Role of Arachidonic Acid Metabolism in Myocardial Ischemia-Reperfusion Injury. Cell Biochem Biophys 2020; 78:255-265. [PMID: 32623640 DOI: 10.1007/s12013-020-00928-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
Abstract
Patients with myocardial ischemic diseases or who are undergoing one of various heart treatments, such as open heart surgery, coronary artery bypass grafting, percutaneous coronary artery intervention or drug thrombolysis, face myocardial ischemia-reperfusion injury (MIRI). However, no effective treatment is currently available for MIRI. To improve the prognosis of people with cardiovascular disease, it is important to research the mechanism of MIRI. Arachidonic acid (AA) is one of the focuses of current research. The various metabolic pathways of AA are closely related to the development of cardiovascular disease, and the roles of various metabolites in ischemia-reperfusion injury have gradually been confirmed. AA is mainly metabolized in the cyclooxygenase (COX) pathway, lipoxygenase (LOX) pathway, and cytochrome P450 monooxygenase (CYP) pathway. This paper summarizes the progress of research on these three major AA metabolic pathways with respect to MIRI.
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Affiliation(s)
- Changjiang Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, PR China.,Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China
| | - Meiling He
- Department of Medicine, Wuhan University, Wuhan, 420100, PR China
| | - Lihua Ni
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China
| | - Ke He
- Department of Cardiology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, PR China
| | - Ke Su
- Department of Cardiology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, PR China
| | - Yinzhi Deng
- Department of Digestive Medicine, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, PR China.
| | - Yuanhong Li
- Department of Cardiology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, PR China.
| | - Hao Xia
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China. .,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, PR China. .,Institute of Cardiovascular Diseases, Wuhan University, Wuhan, 430060, PR China.
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Donkor IO. An update on the therapeutic potential of calpain inhibitors: a patent review. Expert Opin Ther Pat 2020; 30:659-675. [PMID: 32700591 DOI: 10.1080/13543776.2020.1797678] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Calpain is a cytosolic proteinase that regulates of a wide range of physiological functions. The enzyme has been implicated in various pathological conditions including neurodegenerative disorders, cardiovascular disorders, cancer, and several other diseases. Therefore, calpain inhibitors are of interest as therapeutic agents and have been studied in preclinical models of several diseases in which the enzyme has been implicated. AREAS COVERED Calpain inhibitors that were disclosed over the last 5 years (2015-2019) include calpastatin-based peptidomimetics; thalassospiramide lipopeptides; disulfide analogs of alpha-mercaptoacrylic acids; allosteric modulators; azoloimidazolidenones; and macrocyclic/non-macrocyclic carboxamides. The effectiveness of some of the inhibitors in preclinical animal models is discussed. EXPERT OPINION Significant milestones that were made over this time frame include: a) disclosure of novel blood-brain barrier (BBB) permeable calpastatin analogs as calpain inhibitors; b) disclosure that potent calpain inhibitors can be obtained by targeting the hydrophobic pockets on chain A of PEF(S) of the small subunit of calpain; c) use of PEF(S) (PDB ID: 4WQ2) in virtual screening to identify novel structurally diverse calpain inhibitors; and d) mitigation of the metabolic instability of the alpha-ketoamide warhead of calpain inhibitors.
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Affiliation(s)
- Isaac O Donkor
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Pharmacy , Memphis, Tennessee, United States
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Bashtawi Y, Almuwaqqat Z. Therapeutic Hypothermia in STEMI. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2020; 29:77-84. [PMID: 32807668 DOI: 10.1016/j.carrev.2020.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/16/2020] [Accepted: 08/04/2020] [Indexed: 11/26/2022]
Abstract
In this review article we tried to find an answer to the question, should local coronary hypothermia be a part of the early reperfusion strategy in patients with STEMI to prevent reperfusion injury, no-reflow phenomenon, and to reduce the infarct size and mortality. Hypothermia can save cardiomyocytes if achieved in a timely fashion before reperfusion. Intracoronary hypothermia can be adjunct to PCI by lessening ischemia/reperfusion injury on cardiomyocytes and reduction in infarct size. Reperfusion induced Calcium overload, generation of ROS and subsequent activation of Mitochondrial permeability transition pore (MPT) are major contributors to reperfusion injury. Hypothermia reduces calcium loading of the cell and maintains cellular energy and tissue level glucose which can scavenger ROS. Hypothermia reduces MPT activation and thus reduces infarct size. Systemic cooling trials failed to reduce infarct size, perhaps because the target temperature was not reached fast enough, and it was associated with systemic side effects. The need for rapid induction of hypothermia to <35 °C with the ethical concern of delaying reperfusion while cooling the patient and the inconsistency of endovascular cooling results lead to a belief that endovascular cooling may exceed the acceptable level of invasiveness in the context of other novels cardioprotective, regenerative and reperfusion therapies. Clinical trials showed the safety and feasibility of novel intracoronary hypothermia with rapid induction and maintenance of hypothermia using routine PCI equipment ahead of reperfusion. Two phases of cooling were applied without significant delay in the door to balloon time. Cooling of the coronary artery leads to cooling of its dependant myocardium without affecting adjacent myocardium. Heat transfer occurred by heat conduction during the occlusion phase and heat convention during the reperfusion phase. Fine-tuning of saline temperature and infusion rate helped to improve the protocol. The best duration of hypothermia before and after reperfusion is not known and needs further investigation. A balance between the undoubted cardioprotective effects of hypothermia with iatrogenic prolongation of ischemia time needs to be established. A reduction in infarct size was observed but needs to be validated with large randomized trials. Furthermore, it might be possible to augment the cardioprotective effects of intracoronary hypothermia by combination with other cardioprotective approaches such as antioxidant drugs and afterload reducing agents.
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Affiliation(s)
- Yazan Bashtawi
- Department of Medicine, King Hussein Cancer Center, Amman, Jordan.
| | - Zakaria Almuwaqqat
- Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, United States of America
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Abstract
Despite the increasing use and success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Myocardial infarct size is a major determinant of prognosis in these patients. Therefore, cardioprotective strategies aim to reduce infarct size. However, a perplexing gap exists between the many preclinical studies reporting infarct size reduction with mechanical and pharmacological interventions and the poor translation into better clinical outcomes in patients. This Review revisits the pathophysiology of myocardial ischaemia-reperfusion injury, including the role of autophagy and forms of cell death such as necrosis, apoptosis, necroptosis and pyroptosis. Other cellular compartments in addition to cardiomyocytes are addressed, notably the coronary microcirculation. Preclinical and clinical research developments in mechanical and pharmacological approaches to induce cardioprotection, and their signal transduction pathways, are discussed. Additive cardioprotective interventions are advocated. For clinical translation into treatments for patients with acute myocardial infarction, who typically are of advanced age, have comorbidities and are receiving several medications, not only infarct size reduction but also attenuation of coronary microvascular obstruction, as well as longer-term targets including infarct repair and reverse remodelling, must be considered to improve patient outcomes. Future clinical trials must focus on patients who really need adjunct cardioprotection, that is, those with severe haemodynamic alterations.
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CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts. Cell Death Dis 2020; 11:388. [PMID: 32439852 PMCID: PMC7242471 DOI: 10.1038/s41419-020-2605-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 01/05/2023]
Abstract
Previous studies indicated that Ca2+/calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca2+-regulated protease μ-calpain to promote myocardial ischemia/reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca2+ flux using ryanodine and thapsigargin failed to prevent Ca2+ paradox-induced heart injury. In contrast, the Ca2+ paradox increased CaMKII auto-phosphorylation at Thr287, while the CaMKII inhibitor KN-62 and the Na+/Ca2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of μ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.
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The Role of Proteostasis in the Regulation of Cardiac Intercellular Communication. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1233:279-302. [DOI: 10.1007/978-3-030-38266-7_12] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Ponce JM, Coen G, Spitler KM, Dragisic N, Martins I, Hinton A, Mungai M, Tadinada SM, Zhang H, Oudit GY, Song L, Li N, Sicinski P, Strack S, Abel ED, Mitchell C, Hall DD, Grueter CE. Stress-Induced Cyclin C Translocation Regulates Cardiac Mitochondrial Dynamics. J Am Heart Assoc 2020; 9:e014366. [PMID: 32248761 PMCID: PMC7428645 DOI: 10.1161/jaha.119.014366] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/24/2020] [Indexed: 12/14/2022]
Abstract
Background Nuclear-to-mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. In this study, we determined that cyclin C, a component of the Mediator complex, regulates cardiac and mitochondrial function in part by modifying mitochondrial fission. We tested the hypothesis that cyclin C functions as a transcriptional cofactor in the nucleus and a signaling molecule stimulating mitochondrial fission in response to stimuli such as cardiac ischemia. Methods and Results We utilized gain- and loss-of-function mouse models in which the CCNC (cyclin C) gene was constitutively expressed (transgenic, CycC cTg) or deleted (knockout, CycC cKO) in cardiomyocytes. The knockout and transgenic mice exhibited decreased cardiac function and altered mitochondria morphology. The hearts of knockout mice had enlarged mitochondria with increased length and area, whereas mitochondria from the hearts of transgenic mice were significantly smaller, demonstrating a role for cyclin C in regulating mitochondrial dynamics in vivo. Hearts from knockout mice displayed altered gene transcription and metabolic function, suggesting that cyclin C is essential for maintaining normal cardiac function. In vitro and in vivo studies revealed that cyclin C translocates to the cytoplasm, enhancing mitochondria fission following stress. We demonstrated that cyclin C interacts with Cdk1 (cyclin-dependent kinase 1) in vivo following ischemia/reperfusion injury and that, consequently, pretreatment with a Cdk1 inhibitor results in reduced mitochondrial fission. This finding suggests a potential therapeutic target to regulate mitochondrial dynamics in response to stress. Conclusions Our study revealed that cyclin C acts as a nuclear-to-mitochondrial signaling factor that regulates both cardiac hypertrophic gene expression and mitochondrial fission. This finding provides new insights into the regulation of cardiac energy metabolism following acute ischemic injury.
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MESH Headings
- Animals
- CDC2 Protein Kinase/antagonists & inhibitors
- CDC2 Protein Kinase/metabolism
- Cells, Cultured
- Cyclin C/deficiency
- Cyclin C/genetics
- Cyclin C/metabolism
- Disease Models, Animal
- Energy Metabolism/drug effects
- Humans
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Mitochondrial Dynamics/drug effects
- Myocardial Reperfusion Injury/genetics
- Myocardial Reperfusion Injury/metabolism
- Myocardial Reperfusion Injury/pathology
- Myocardial Reperfusion Injury/prevention & control
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Protein Kinase Inhibitors/pharmacology
- Protein Transport
- Rats, Wistar
- Signal Transduction
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Affiliation(s)
- Jessica M. Ponce
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
- Interdisciplinary Graduate Program in GeneticsUniversity of IowaIowa CityIA
| | - Grace Coen
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
| | - Kathryn M. Spitler
- Department of BiochemistryCarver College of MedicineUniversity of IowaIowa CityIA
| | - Nikola Dragisic
- Stead Family Department of PediatricsUniversity of IowaIowa CityIA
| | - Ines Martins
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
| | - Antentor Hinton
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
- Fraternal Order of Eagles Diabetes Research CenterDivision of Endocrinology and MetabolismCarver College of MedicineUniversity of IowaIowa CityIA
| | - Margaret Mungai
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
- Fraternal Order of Eagles Diabetes Research CenterDivision of Endocrinology and MetabolismCarver College of MedicineUniversity of IowaIowa CityIA
| | - Satya Murthy Tadinada
- Department of Pharmacology and Iowa Neuroscience InstituteCarver College of MedicineUniversity of IowaIowa CityIA
| | - Hao Zhang
- Mazankowski Alberta Heart Institute Canada Research Chair in Heart FailureDivision of Cardiology2C2 Walter Mackenzie Health Sciences Centre EdmontonAlbertaCanada
| | - Gavin Y. Oudit
- Mazankowski Alberta Heart Institute Canada Research Chair in Heart FailureDivision of Cardiology2C2 Walter Mackenzie Health Sciences Centre EdmontonAlbertaCanada
| | - Long‐Sheng Song
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
- Fraternal Order of Eagles Diabetes Research CenterDivision of Endocrinology and MetabolismCarver College of MedicineUniversity of IowaIowa CityIA
- Iowa City Veterans Affairs Medical CenterIowa CityIA
| | - Na Li
- Department of Cancer BiologyDana‐Farber Cancer InstituteBostonMA
- Department of GeneticsHarvard Medical SchoolBostonMA
| | - Peter Sicinski
- Department of Cancer BiologyDana‐Farber Cancer InstituteBostonMA
- Department of GeneticsHarvard Medical SchoolBostonMA
| | - Stefan Strack
- Department of Pharmacology and Iowa Neuroscience InstituteCarver College of MedicineUniversity of IowaIowa CityIA
| | - E. Dale Abel
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
- Fraternal Order of Eagles Diabetes Research CenterDivision of Endocrinology and MetabolismCarver College of MedicineUniversity of IowaIowa CityIA
| | - Colleen Mitchell
- Department of Mathematics and Delta CenterUniversity of IowaIowa CityIA
| | - Duane D. Hall
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
| | - Chad E. Grueter
- Abboud Cardiovascular Research CenterDivision of Cardiovascular MedicineDepartment of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA
- Interdisciplinary Graduate Program in GeneticsUniversity of IowaIowa CityIA
- Fraternal Order of Eagles Diabetes Research CenterDivision of Endocrinology and MetabolismCarver College of MedicineUniversity of IowaIowa CityIA
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Hausenloy D, Davidson SM. David Garcia-Dorado: a true pioneer in cardiac ischaemia/reperfusion injury. Cardiovasc Res 2019; 115:e177-e180. [PMID: 31647537 DOI: 10.1093/cvr/cvz282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Derek Hausenloy
- The Hatter Cardiovascular Institute, University College London, London, UK.,Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore.,National Heart Research Institute Singapore, National Heart Centre, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University Singapore, Singapore.,The National Institute of Health Research, University College London Hospitals, Biomedical Research Centre, Research & Development, London, UK.,Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, London, UK
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