Abstract 3987: ARC Attenuates Left Ventricular Dysfunction and Reduces Mortality in a Murine Model of Heart Failure
Apoptosis Repressor with Caspase recruitment domain (ARC) is an endogenous inhibitor of cell death that is highly expressed in cardiac myocytes. ARC uniquely inhibits both extrinsic (death receptor) and intrinsic (mitochondrial/ER) apoptosis pathways. Cardiac myocyte loss by apoptosis plays a crucial role in myocardial infarction and heart failure. We sought to investigate potential roles of ARC in limiting myocardial infarct size and post infarct remodeling in mouse models of left coronary artery (LCA) ischemia-reperfusion (I/R) and permanent LCA occlusion in vivo. Mouse lacking ARC were created by homologous recombination and exhibited no baseline abnormalities. Surprisingly, absence of ARC did not exacerbate myocardial infarct size following 30, 45, or 60 min of ischemia followed by 24 h reperfusion in both C57Bl6 and FVB backgrounds. This result proved not to be due to redundancy but rather to dramatic decreases in ARC protein levels triggered by the oxidative stress of reperfusion (shown in our other work to be due to ARC degradation in the proteasome). Accordingly, we hypothesized that maintenance of ARC levels would suffice to be cardioprotective. To test our hypothesis, we generated mice with cardiac-specific, doxycycline controlled, ARC overexpression and subjected them to 45 minute ischemia and 24 h, 3 d or 7 d reperfusion. ARC overexpression led to 40% reduction in infarct size (P<0.001). Left ventricular ejection fraction, measured by echocardiography at 3 d and 7 d, was significantly higher in ARC overexpressing mice compared to wild type littermates. Furthermore, ARC overexpression preserved left ventricular (LV) dimensions and reduced inflammation and fibrosis. In contrast to I/R, infarct size resulting from permanent LCA occlusion was not altered by ARC overexpression. However, ARC ameliorated post-infarct remodeling, and significantly improved survival following permanent LCA occlusion. These results indicate that ARC limits infarct size following I/R and lessens post-infarct pathological remodeling and mortality.