title: Ryanodine receptor leak mediated by caspase-8 activation leads to left ventricular injury after myocardial ischemia-reperfusion.
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.
authors.affiliation: Institut de la Santé et de la Recherche Médicale, U1046, F-34295 Montpellier, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Albano C
authors.initials: AC
authors.lastname: Meli
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roberge
authors.forename: Jian
authors.initials: J
authors.lastname: Shan
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rauzier
authors.forename: Alexandre
authors.initials: A
authors.lastname: Marchand
authors.forename: David
authors.initials: D
authors.lastname: Chauvier
authors.forename: Cécile
authors.initials: C
authors.lastname: Cassan
authors.forename: Christine
authors.initials: C
authors.lastname: Crozier
authors.forename: Patrice
authors.initials: P
authors.lastname: Bideaux
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.forename: Etienne
authors.initials: E
authors.lastname: Jacotot
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism*; D004789:Enzyme Activation; D005453:Fluorescence; D006352:Heart Ventricles / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010617:Phenanthridines / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D020257:Ventricular Remodeling
chemical_list: C521281:5-(6'-triphenylphosphoniumhexyl)-5,6-dihydro-6-phenyl-3,8-phenanthridinediammine; D010617:Phenanthridines; D019837:Ryanodine Receptor Calcium Release Channel; D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8