Abstract 12104: Treatment With Exogenous Atrial Natriuretic Peptide Ameliorates Myocardial Insulin Resistance and Protects Against Ischemia-Reperfusion Injury in Diet-Induced Obesity

Abstract

Increasing evidence suggests natriuretic peptide (NP) coordinate inter-organ metabolic crosstalk in addition to its classical actions on hemodynamic regulation. We recently reported exogenous atrial NP (ANP) treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and by attenuating hepatic steatosis in diet-induced obesity. We herein hypothesized that exogenous ANP treatment also ameliorates insulin resistance of the myocardium in which endogenous NP is produced, leading to the cardioprotection during ischemia-reperfusion injury (IRI) in diet-induced obesity. The mice fed a high fat diet (HFD) or normal fat diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously via osmotic pump for another 3 weeks (0.5 μg/kg/min). Intraperitoneal administration of insulin induced Akt phosphorylation in NFD hearts, which was reduced in HFD. ANP treatment restored the impaired insulin-induced Akt phosphorylation in HFD hearts, suggesting that exogenous ANP ameliorated myocardial insulin resistance. To test the functional significance of this, hearts were exposed to IRI using Langendorff model. After IRI, HFD resulted in an impaired left ventricular developed pressure (LVDP) recovery with corresponding increase in infarct size. However, ANP treatment improved functional recovery and reduced injury along with restoration of the impaired IRI-induced Akt phosphorylation in HFD hearts. (% LVDP recovery of baseline: NFD 62.9%±3.6 <n=8>, NFD+ANP 64.5%±4.2% <n=8>, HFD 20.8%±3.3 <n=9>, HFD+ANP 31.4%±2.8% <n=9>, p<0.05) Myocardial ultrastructural analyses by electron microscopy showed number of peri-mitochondrial lipid droplets was increased in HFD treated with ANP, suggesting that ANP protects mitochondria from lipid overload. Of note, ANP treatment substantially attenuated mitochondria cristae disruption after IRI in HFD hearts. In conclusion, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with restoration of disrupted mitochondrial structure in diet-induced obesity. The findings that exogenous NP has significant impact on the NP-rich failing myocardium provide new insight into the biological properties and dynamics of NP.