A selective mineralocorticoid receptor blocker, esaxerenone, attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein e-deficient mice

Abstract

Abstract Introduction Pharmacological blockade of mineralocorticoid receptors (MR) is a potential therapeutic approach to reduce cardiovascular complications because MR play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vascular function. We investigated the effects of a novel non-steroidal selective MR blocker, esaxerenone (ESAX), recently approved for hypertension treatment in Japan, on vascular function and the development of atherosclerosis. Methods and results ESAX (3mg/kg/day) or vehicle was orally administered to western type diet-fed apolipoprotein E-deficient mice for 20 weeks or for 8 weeks to investigate the effects on atherogenesis or vascular dysfunction. Administration of ESAX for 20 weeks suppressed the development of atherosclerotic plaques in the aortic arch compared with the vehicle group (p<0.001) without alteration of blood pressure. In addition, ESAX reduced the expression of intercellular cell adhesion molecule-1 (p<0.05), macrophage infiltration (p<0.01), lipid deposition (p<0.05) and tended to decrease the expression of vascular cell adhesion molecule-1 as determined by immunohistochemical analysis. Moreover, phosphorylation of eNOSSer1177 (p<0.05) and Akt (p<0.05) were increased in the aorta of ESAX-treated mice. Administration of ESAX for 8 weeks attenuated western type diet-induced endothelial dysfunction (p<0.05) accompanied with the decrease in expression of ICAM1 (p<0.05) and phosphorylation of JNK (p<0.05) in the descending aorta. In in vitro experiment, aldosterone decreased the phosphorylation of eNOSSer1177 and increased the phosphorylation of eNOSThr495 in a dose dependent manner, which were attenuated by ESAX in HUVECs. In ex vivo vascular reactivity assay, ESAX diminished the aldosterone-induced endothelial dysfunction. Conclusion ESAX ameliorated hyperlipidemia-induced atherosclerosis and vascular dysfunction in mice, suggesting that ESAX is a promising therapeutic approach for cardiovascular complications.