Deletion of Smooth Muscle, but not Endothelial, Mineralocorticoid Receptors Prevents Obesity‐Associated Coronary Vascular Dysfunction in Females

Abstract

Coronary vascular dysfunction is an independent predictor of cardiac mortality in obesity and diabetes, both of which are associated with inappropriate activation of the renin‐angiotensin‐aldosterone system (RAAS). We recently demonstrated that systemic mineralocorticoid receptor (MR) blockade with spironolactone treats coronary vascular dysfunction in male Zucker Obese rat model. The aim of the present study was to investigate MR involvement in coronary dysfunction induced by western diet (WD) feeding in female mice, via both systemic blockade and using vascular cell‐specific MR knockout (KO) mice. Female C57BL/6J, endothelial cell (EC)‐specific MR KO mice, and smooth muscle cell (SMC)‐specific MR KO mice were fed either control diet or WD for 16 weeks. Systemic MR blockade was achieved in a group of WD fed C57BL/6J mice via spironolactone (Spiro; sc, 20 mg/kg/d) treatment for 16 weeks. Mice were 28–32 weeks of age at study completion. WD feeding induced obesity, hyperinsulinemia, hyperglycemia, glucose intolerance and adipose inflammation, but did not change blood pressure. Coronary vascular function was assessed via wire myography of left ventricular coronary arteries. Coronary endothelium‐dependent vasodilation to acetylcholine (ACh) was impaired by WD feeding and this was prevented by Spiro treatment and in SMC MR KO mice fed a WD, independent of blood pressure. Pretreatment of coronary arteries with the superoxide dismutase mimetic Tempol restored maximal dilation to ACh in WD fed mice. EC MR KO had no effect on coronary function in mice fed control diet or WD. Endothelium‐independent vasodilation to sodium nitroprusside was principally unaffected by WD feeding. Furthermore, in SMC MR KO mice, WD‐induced enhancement of coronary vasoconstriction to the thromboxane mimetic U46619 was prevented. Additional studies revealed that WD feeding increased gene markers of endothelial inflammation (ICAM‐1, PECAM) and fibrosis (collagen I) in aorta and that this is prevented in SMC MR KO mice fed a WD. SMC MR deletion did not, however, attenuate WD‐induced visceral adipose inflammation or glucose intolerance. Taken together, this study confirms and extends our previous findings regarding MR involvement in obesity‐associated coronary vascular endothelial dysfunction. Specifically, these data provide further insight into the mechanisms underlying the beneficial effects of MR antagonism in obesity, in particular highlighting a novel role of SMC MR, but not EC MR, as an important mediator in the development of obesity‐associated coronary vascular dysfunction.Support or Funding InformationFunded by VHA BLR&D BX002030 (SBB) and NIH NHLBI R01 HL119290 (IZJ).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.