Abstract 131: Endothelial Cell Mineralocorticoid Receptor: A Critical Player in Aortic Stiffness and Cardiac Diastolic Dysfunction in Female Mice

Abstract

Enhanced activation of mineralocorticoid receptors (MRs) impairs insulin metabolic signaling, increases oxidative stress, and induces maladaptive immune responses with associated CV abnormalities. Emerging information suggests that obesity and insulin resistance predict CV stiffness in females. However, the specific role of endothelial cell MR (ECMR) has not been explored. Accordingly, we hypothesized that ECMR signaling modulated by a western diet (WD) impairs insulin signaling and increases inflammation, fibrosis and CV stiffness in females. Four week-old ECMR knockout (ECMR -/- ) and wild-type female mice were fed a mouse chow or WD containing fat (46%), sucrose (17.5%), and high fructose (17.5%) for 16 weeks. WD prompted MR to bind the hormone response element (nGnACAnnnTGTnCn) on the site of ENaC promoter and induced an increase in ENaC expression that was associated with increased aortic and EC stiffness as determined by in vivo pulse wave velocity and ex vivo atomic force microscopy techniques, respectively The elevated aortic stiffness was accompanied by increased expression of cytokines IL-17, MCP-1 and M1 markers CD 86, and CD11c. ENaC expression was reduced in the ECMR -/- vasculature with a decrease in WD-increase in aortic and EC stiffness.. ECMR -/- also improved aortic vasorelaxation to Ach, SNP (10 -9 -10 -4 mol/L), and insulin (0.1- 300 ng/ml), which were impaired by WD. Additionally, ECMR -/- restored WD-induced cardiac diastolic dysfunction assessed by cardiac MRI and echocardiography. Diastolic dysfunction was related to cardiomyocyte hypertrophy, oxidative stress, and fibrosis and occurred with enhanced activation of S6 kinase-1, Erk 1/2, serine phosphorylation of IRS-1, inactivation of PI3K-AKT-eNOS signaling pathways and the pro-fibrotic TGF-β1/ Smad signaling pathway and increased macrophage pro-inflammatory polarization. ECMR -/- markedly attenuated the cardiac functional and changes signaling induced by WD. These findings suggest that increased ECMR signaling and associated ENaC activation plays a key role in WD induced insulin metabolic sinaling impairment, adaptive pro-inflammatory responses, macrophage polarization and associated aortic stiffness and cardiac diastolic dysfunction in females.