Abstract 342: Increased Myocardial Ischemic/Reperfusion Injury in Renal Failure Involves Cardiac Adiponectin Signal Deficiency

Abstract

Chronic kidney disease (CKD) is associated with increased incidence as well as adverse outcomes of acute myocardial infarction. Adiponectin (APN), known as a cardioprotective factor, has been observed decreased in cardiovascular disorders including myocardial infarction. However, plasma APN levels are significantly increased and are inversely related to the risk of cardiovascular morbidity and mortality in patients with CKD. The mechanism underlying the paradoxical relationship between high APN and poor cardiac outcome remains unclear. In the present study, subtotal nephrectomized (SN) and sham-operated mice were randomly subjected to a 30 min myocardial ischemia followed by 24 hrs reperfusion with or without human recombinant gAd treatment (2μg/g/d, 7days). Compared with sham WT mice, SN mice displayed significantly depressed cardiac function and enlarged infarct size following MI/R. TUNEL staining and caspase-3 activity assay demonstrated markedly increased cardiomyocyte apoptosis in SN mice following MI/R. What’s more, increased plasma total APN levels was observed in SN mice 4 weeks after MI/R. Importantly, SN caused further decreased cardiac function and larger infarct size in APN knockout (KO) mice compared with those in SN WT mice subjected to MI/R. However, gAd treatment significantly enhanced cardiac function and reduced infarct size and apoptosis in both WT and KO mice. Further, we found that SN KO mice showed more reduced eNOS phosphorylation, upregulated iNOS expression and ·O 2 - production and consequently increased peroxynitrite production in cardiac tissue than SN WT animals, which can be partly reversed by administration of gAd. AdipoR1 expression was reduced 4-wk after SN whereas AdipoR2 showed no significant change. More importantly, AMPK activation was also inhibited after SN and exogenous gAd supplementation reversed this change. In conclusion, the present study demonstrates that renal dysfunction increases cardiac susceptibility to ischemic/reperfusion injury, which is associated with downregulated APN/AdipoR1/AMPK signaling and increased oxidative/nitrative stress in local myocardium, and provides the first evidence for the benefits of exogenous supplement of APN on cardiac outcomes in renal failure.