Abstract 14119: Contrasting Effects of Exercise Training After Acute Myocardial Infarction versus Aortic Stenosis Depend Critically on the Regulation of Endothelial Nitric Oxide Synthase

Abstract

Introduction: The cardiovascular benefits of exercise training (EX) are widely appreciated. Previously we found that the cardiac effects of EX critically depend on the underlying cause of heart disease. Hypothesis: The underlying etiology determines how EX affects the endothelial nitric oxide (NO) synthase (eNOS)-mediated balance between NO and superoxide (O2-). Methods: Mice were subjected to sham surgery, myocardial infarction (MI) or transverse aortic constriction (TAC), and subsequently exposed to 8 weeks of voluntary wheel running or sedentary housing. Left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements; fibrosis by Picro-sirius Red staining; peroxynitrite (ONOO-) and O2- production by luminol- and lucigenin-enhanced chemiluminescence respectively, with or without the NOS inhibitor L-NAME; eNOS uncoupling and eNOS S-glutathionylation by western blot and coimmunoprecipitation, respectively; cardiac NO by the Griess reaction. Results: EX ameliorated LV dysfunction and fibrosis in MI but not TAC (Table 1). Strikingly, O2- generation was blunted by EX in MI, but exacerbated by EX in TAC, which was largely NOS-dependent. Accordingly, eNOS uncoupling and eNOS S-glutathionylation were corrected by EX in MI but aggravated in TAC mice. In parallel, ONOO- levels was attenuated by EX in MI but aggravated by EX in TAC. Cardiac NO levels were reduced in MI and TAC and normalized by EX in MI. Conclusions: The contrasting effects of EX in MI vs TAC can be explained by the highly divergent effects of EX on eNOS regulation, resulting in blunted vs aggravated oxidative stress by EX in MI vs TAC.