Esaxerenone Attenuates Atherogenesis and Vascular Dysfunction in Apolipoprotein E-Deficient Mice

The pharmacological blockade of mineralocorticoid receptors (MR) is a potential therapeutic approach to reduce cardiovascular complications. Recent studies suggest that MR blockers affect several extrarenal tissues, including vascular function. We investigated the effects of a novel non-steroidal selective MR blocker, esaxerenone, on vascular function and atherogenesis.Esaxerenone (3 mg/kg/day) was orally administered for 20 weeks or vehicle for 8 weeks to apolipoprotein E-deficient (ApoE^-/-) mice fed a Western-type diet to investigate the effects on atherogenesis or vascular dysfunction. Human umbilical vein endothelial cells (HUVEC) were used to perform in vitro experiments.Administration of esaxerenone 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, esaxerenone significantly reduced the expression of intercellular cell adhesion molecule-1, macrophage infiltration, and lipid deposition as determined by immunohistochemical analysis. Moreover, phosphorylation of eNOS^Ser1177 and Akt were increased in the aorta of esaxerenone-treated mice. Administration of esaxerenone for 8 weeks attenuated Western-type diet-induced endothelial dysfunction, accompanied by a decrease in expression of ICAM-1 and phosphorylation of JNK in the descending aorta. In an ex vivo vascular reactivity assay using ApoE^-/- aortic rings, esaxerenone diminished aldosterone-induced endothelial dysfunction. In an in vitro experiment, aldosterone decreased the phosphorylation of eNOS^Ser1177 and increased the phosphorylation of eNOS^Thr495 in a dose-dependent manner, which were attenuated by esaxerenone in HUVECs.Esaxerenone ameliorated hyperlipidemia-induced atherosclerotic plaque progression and vascular dysfunction in ApoE^-/- mice, suggesting that esaxerenone is a promising therapeutic approach for cardiovascular complications.