Ryanodine receptor leak mediated by caspase-8 activation leads to left ventricular injury after myocardial ischemia-reperfusion

Jérémy Fauconnier, Albano C. Meli, Jérôme Thireau, Stephanie Roberge, Jian Shan, Yassine Sassi, Steven R. Reiken, Jean Michel Rauzier, Alexandre Marchand, David Chauvier, Cécile Cassan, Christine Crozier, Patrice Bideaux, Anne Marie Lompré, Etienne Jacotot, Andrew R. Marks, Alain Lacampagne

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81 Scopus citations


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 Ca2+ and redox homeostasis. In this study, we sought to determine how acute inflammatory response contributes to reperfusion injury and Ca2+ 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) Ca2+ leak. Pharmacological inhibition of caspase-8 before reperfusion with Q-LETD-OPh or prevention of calstabin2 depletion from the RyR2 complex with the Ca2+ channel stabilizer S107 ("rycal") inhibited the SR Ca2+ 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 Ca2+ leak trough normalization of RyR2 function is cardioprotective.

Original languageEnglish
Pages (from-to)13258-13263
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number32
StatePublished - 9 Aug 2011
Externally publishedYes


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