Abstract 16412: Aldosterone Blockade Promotes The Stability of the Apoptosis Repressor Arc After Reperfusion Injury - A New Strategy for Management of Ischemic Disease
Apoptosis is an important mechanism of cardiac myocyte loss during ischemia-reperfusion injury and heart failure. We have identified the endogenous myocyte inhibitor of apoptosis ARC (Apoptosis Repressor with Caspase recruitment domain) is essential for minimizing cardiac damage post-infarction. The mechanisms by which ARC protects the myocardium basally are incompletely understood. However, ARC is degraded quickly, via ubiquitination and proteosomal targeting, upon reperfusion injury which permits onset of the associated apoptosis. Thus, we sought to determine the role of ARC in myocardial health and the primary stimulus responsible for its degradation after infarction. ARC abrogated DNA cleavage induced by multiple apoptotic stimuli. Using antibody arrays we discovered ARC interacts with key facilitators of apoptotic nuclear remodeling (ICAD, acinus and helicard) and prevents their activation by executioner caspases by limiting access of the protease to the putative cleavage site. The functional importance of these interactions were demonstrated by the inability of ARC null mice (simulates loss of ARC post-infarction) to prevent nuclear remodeling after sub-maximal reperfusion injury (30 min infarction, 15 min reperfusion) in vivo with 5 fold more processing of ICAD/acinus/helicard than Wt mice. Thus, preventing ARC degradation during reperfusion would salvage the myocardium. To this end we have identified aldosterone as a novel and perhaps the most significant pathological regulator of ARC degradation post-reperfusion injury. We found that aldosterone aggravates reperfusion injury and promotes ARC degradation in vitro and ex vivo. Moreover, ARC was found to be essential for the anti-apoptotic effects and salvage properties of aldosterone receptor blockade with spironolactone. The fact that blockade of aldosterone receptors significantly reduces mortality post-infarction indicates that this is a promising therapy by which to control the loss of ARC, and therefore apoptosis, in response to myocardial infarction. In conclusion, salvage of ARC expression and activity is a novel and readily achievable mechanism by which the after effects of infarction can be targeted therapeutically for patient benefit.
- © 2013 by American Heart Association, Inc.