1. Ryanodine receptor leak mediated by caspase-8 activation leads to left ventricular injury after myocardial ischemia-reperfusion
- Author
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Jean-Michel Rauzier, Stéphanie Roberge, Anne-Marie Lompré, Jérémy Fauconnier, Yassine Sassi, Jérôme Thireau, David Chauvier, Etienne Jacotot, Patrice Bideaux, Cécile Cassan, Albano C. Meli, Steven Reiken, Alexandre Marchand, Christine Crozier, Jian Shan, Alain Lacampagne, Andrew R. Marks, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institute of pharmacology and toxicology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Department of Physiology & Cellular Biophysics, Columbia University [New York], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Theraptosis Research Laboratory, Theraptosis S.A., Department of Reproductive Biology, Imperial College London, Columbia University College of Physicians and Surgeons, and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN)
- Subjects
Mitochondrial ROS ,medicine.medical_specialty ,Heart Ventricles ,Diastole ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Ryanodine receptor 2 ,Rats, Inbred WKY ,Fluorescence ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Myocardial infarction ,Ventricular remodeling ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Caspase 8 ,Multidisciplinary ,Ventricular Remodeling ,Ryanodine receptor ,business.industry ,Tumor Necrosis Factor-alpha ,Myocardium ,Ryanodine Receptor Calcium Release Channel ,Biological Sciences ,medicine.disease ,Phenanthridines ,Rats ,Enzyme Activation ,chemistry ,Cardiology ,cardiovascular system ,business ,Reperfusion injury - Abstract
Myocardial ischemic disease is the major cause of death worldwide. After myocardial infarction, reperfusion of infracted heart has been an important objective of strategies to improve outcomes. However, cardiac ischemia/reperfusion (I/R) is characterized by inflammation, arrhythmias, cardiomyocyte damage, and, at the cellular level, disturbance in Ca 2+ and redox homeostasis. In this study, we sought to determine how acute inflammatory response contributes to reperfusion injury and Ca 2+ homeostasis disturbance after acute ischemia. Using a rat model of I/R, we show that circulating levels of TNF-α and cardiac caspase-8 activity were increased within 6 h of reperfusion, leading to myocardial nitric oxide and mitochondrial ROS production. At 1 and 15 d after reperfusion, caspase-8 activation resulted in S-nitrosylation of the RyR2 and depletion of calstabin2 from the RyR2 complex, resulting in diastolic sarcoplasmic reticulum (SR) Ca 2+ leak. Pharmacological inhibition of caspase-8 before reperfusion with Q-LETD-OPh or prevention of calstabin2 depletion from the RyR2 complex with the Ca 2+ channel stabilizer S107 (“rycal”) inhibited the SR Ca 2+ leak, reduced ventricular arrhythmias, infarct size, and left ventricular remodeling after 15 d of reperfusion. TNF-α–induced caspase-8 activation leads to leaky RyR2 channels that contribute to myocardial remodeling after I/R. Thus, early prevention of SR Ca 2+ leak trough normalization of RyR2 function is cardioprotective.
- Published
- 2011