Eplerenone stimulates eNOS through VEGF and inhibiting iNOS via NF-kappaB induced by the oxidative stress-LOX-1 pathway

Abstract

Stimulating endothelial cells with vascular endothelial growth factor (VEGF) activates endothelial nitric oxide synthase (eNOS) and regulation of inducible NOS (iNOS) expression is mediated via nuclear factor-kappaB (NF-kappaB). We investigated the impact of eplerenone, a novel selective aldosterone blocker, on cardiac dysfunction and cardiovascular remodeling in Dahl salt-sensitive (DS) rats with heart failure. Specifically, we hypothesized that eplerenone stimulates eNOS through VEGF and inhibits iNOS via NF-kappaB following the development of oxidative stress and activation of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway. Eplerenone (10, 30, and 100 mg/kg/day) or vehicle was given from left ventricular hypertrophy stage (11 weeks) to failing stage (18 weeks) for 7 weeks. Decreased fractional shortening in failing rats was significantly ameliorated by eplerenone treatment. Downregulated eNOS and VEGF expression in the DS rats was increased by eplerenone. Upregulated expression of iNOS, LOX-1, NAD(P)H oxidase p22 phox, p47 phox, gp91 phox and activated p65 NF-kappaB phosphorylation in DS rats was inhibited by eplerenone. Eplerenone administration resulted in significantly improvement of cardiac function and remodeling and suppression of atrial natriuretic peptide expression. These results suggest that the cardioprotective effects of eplerenone may be mediated in part by reducing oxidative stress by stimulating eNOS through VEGF and inhibiting iNOS via NF-kappaB following activation of the LOX-1 pathway.