Abstract 1668: Low-dose Eplerenone Down-regulates Caveolin-1 and Improves Endothelial Function by Mechanisms Independent of MR Antagonism
Metabolic syndrome (MS) is associated with increased cardiovascular morbidity and mortality. One of the early pathogenetic events associated with it is endothelial dysfunction. Patients with MS often exhibit higher levels of LDL-cholesterol, which is linked to the expression of caveolin-1 (cav1) that play roles as a negative regulator of eNOS. Recently, a selective mineralocorticoid receptor (MR) blocker, eplerenone (Epl), has been shown to ameliorate various cardiovascular disorders, although the exact mechanisms involved remain unclear. In this study, we examined the effect of low-dose Epl on endothelial function in a rat model of MS and cultured endothelial cells (ECs) to determine the cav1 expression level. Epl (30 mg/kg/day; Epl group) or vehicle (Vcl group) was orally administered to SHR/NDmcr-cp (SHRcp), a rat model of MS, for four weeks. We measured blood pressure and metabolic and oxidative stress markers in the urine and blood, and evaluated tension of the aortic rings as well as aortic cav1 levels. The effect of Epl on cav1 and eNOS expression, as well as on NO production, was also analyzed in cultured ECs. Body weight, blood pressure, metabolic and oxidative stress markers, and endothelium-independent relaxation were no different between the Vcl and Epl groups. However, the Epl group showed a significant improvement of endothelium-dependent relaxation by acetylcholine, and down-regulation of aortic cav1. The ECs incubated with Epl (1x10−11 to 1x10−7 M) for three days showed no change in eNOS expression, but a marked decrease of cav1 in parallel with increased eNOS phosphorylation at Ser1179 and enhanced NO production evoked by ATP. Importantly, no effect of aldosterone or spironolactone (another MR antagonist) on cav1 expression was seen, indicating that an aldosterone-MR pathway was not involved. Low doses of Epl improve endothelial function in SHRcp independently of blood pressure reduction. MR-independent down-regulation of endothelial cav1 and increased eNOS phosphorylation at Ser1179 by Epl may contribute to such beneficial effects.