P571Ryanodine receptor leak Q: 1 mediated by caspase-8 activation leads to left ventricular injury after myocardial ischemia-reperfusion

    loading  Checking for direct PDF access through Ovid

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 Ca2+ and redox homeostasis. In the present 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 hr of reperfusion leading to myocardial nitric oxide and mitochondrial ROS production. At 1 and 15 days after reperfusion, TNF-α-induced caspase-8 activation resulted in S-nitrosylation of the RyR2 and depletion of calstabin2 (FKBP12.6) from the RyR2 complex resulting in diastolic SR Ca2+ leak. Pharmacological inhibition of caspase-8 prior 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 days of reperfusion. TNF-α-induced caspase-8 activation leads to leaky RyR2 channels that contribute to myocardial remodeling after I/R. Early prevention of SR Ca2+ leak trough normalization of RyR2 function represents a new potential therapeutic strategy in cardioprotection.

Related Topics

    loading  Loading Related Articles