Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females

TLDR

Overnutrition and insulin resistance are prominent risk factors for cardiac diastolic dysfunction in females. The study tests whether excess endothelial cell mineralocorticoid receptor signaling drives Western‑diet–induced diastolic dysfunction and its associated fibrosis, hypertrophy, inflammation, and insulin signaling abnormalities in female mice. Female endothelial cell MR knockout and wild‑type mice, starting at four weeks of age, were fed either standard chow or a Western diet for four months. Western‑diet feeding induced diastolic dysfunction, myocardial fibrosis, hypertrophy, oxidative stress, inflammation, and cardiomyocyte stiffening, all of which were prevented by endothelial cell mineralocorticoid receptor deletion, which also restored insulin signaling and reduced pro‑inflammatory macrophage polarization.

Abstract

Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a Western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation, and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor signaling. Four-week-old female endothelial cell mineralocorticoid receptor knockout and wild-type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion, and increased left ventricular filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that were associated with enhanced profibrotic (transforming growth factor β1/Smad) and progrowth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a proinflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, endothelial cell mineralocorticoid receptor deficiency prevented WD-induced diastolic dysfunction, profibrotic, and progrowth signaling, in conjunction with reductions in macrophage proinflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased endothelial cell mineralocorticoid receptor signaling associated with consumption of a WD plays a key role in the activation of cardiac profibrotic, inflammatory, and growth pathways that lead to diastolic dysfunction in female mice.