Mineralocorticoid Receptor Antagonism Treats Obesity-Associated Cardiac Diastolic Dysfunction

摘要: Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor cardiovascular events for which no evidence-based treatment exists. In light renin-angiotensin-aldosterone system activation in the cardioprotective action mineralocorticoid receptor (MR) antagonists systolic heart failure, we examined hypothesis that MR blockade blood pressure-independent low-dose spironolactone (LSp) would treat obesity-associated DD Zucker obese (ZO) rat. Treatment ZO rats exhibiting established LSp normalized function, assessed by echocardiography. This was associated reduced fibrosis, but not hypertrophy, restoration endothelium-dependent vasodilation isolated coronary arterioles via nitric oxide-independent mechanism. Further mechanistic studies revealed oxidative stress improved endothelial insulin signaling, change arteriolar stiffness. Infusion Sprague-Dawley agonist aldosterone reproduced noted rats. addition, function ZO-LSp attenuated systemic adipose inflammation anti-inflammatory shift immune cell mRNAs. Specifically, increased markers alternatively activated macrophages regulatory T cells. had unchanged pressure, serum potassium, sensitivity, or kidney injury, proteinuria. Taken together, these data demonstrate antagonism effectively treats obesity-related mechanisms. These findings help identify particular population might benefit from antagonist therapy, specifically patients resistance.