Abstract 543: Impact of Eplerenone on Vascular Function in LOX-1 Overexpressing Mice on High-Fat Diet

Abstract

Experimental and clinical studies support a protective effect of aldosterone-binding mineralocorticoid receptor (MR) blockade on heart failure. The impact of MR antagonist eplerenone on endothelial function is less well understood. In this study, we analyzed the effects of high-fat diet (HFD) and MR blockade on metabolic parameters and endothelial function in mice overexpressing the endothelial oxidized LDL receptor LOX-1. Mice were fed standard diet (STD) or HFD with or without MR blocker eplerenone for 20 weeks. In agreement with clinical studies aldosterone plasma levels (LC-MS/MS) were elevated in eplerenone-treated mice. Body weight, epididymal, retroperitoneal, mesenteric and perivascular fat were increased after HFD. Diet-induced obesity elevated triglycerides, total cholesterol, and LDL plasma levels. Total cholesterol/HDL cholesterol ratio was increased in HFD fed LOX-1tg mice and decreased by eplerenone. LDLR-/- and HFD-fed LOX1tg and LOX1tg/LDLR-/- (LOLR) mice showed elevated fasting blood glucose levels compared to STD, which were partially normalized by eplerenone. LDLR-/-, LOX 1tg and LOLR mice had impaired endothelial function in thoracic aortas (Mulvany myograph) compared to C57BL/6J mice. HFD pronounced endothelial dysfunction in LOX-1tg and LOLR mice, which was improved by eplerenone. Reactive oxygen species can limit NO availability and were reduced in aorta and adipose tissues after eplerenone. Using a new method to evaluate flow-mediated dilation with a self-developed Optical Coherence Tomography (OCT) device, we could show endothelial dysfunction in saphenous artery in vivo after HFD. This was not restored by eplerenone. In epididymal white adipose tissue of LOX-1tg mice, HFD increased CD206, CD11c, F4/80, leptin, NADPH oxidase (Nox) 1, 2 and 4 and TNF-α mRNA expression (real-time PCR). Eplerenone treatment had no significant impact on CD11c, F4/80 and IL-6 expression, but elevated anti-inflammatory IL-10. CD206, Nox1, Nox2 and Nox4 expression was reduced by eplerenone in mice on HFD. In conclusion, our data support beneficial effects of MR blockade by eplerenone on endothelial function, metabolic parameters, inflammation and oxidative stress in a proatherosclerotic mouse model overexpressing LOX-1 on HFD.