Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction. Issue 4 (April 2016)

• Record Type: Journal Article
• Authors: Gueret, Alexandre; Harouki, Najah; Favre, Julie; Galmiche, Guillaume; Nicol, Lionel; Henry, Jean-Paul; Besnier, Marie; Thuillez, Christian; Richard, Vincent; Kolkhof, Peter; Mulder, Paul; Jaisser, Frédéric; Ouvrard-Pascaud, Antoine
• Is Part Of: Hypertension. Volume 67:Issue 4(2016:Apr.)
• Publication Date: 2016-04
• Subjects: coronary vessels -- myocardial infarction -- receptors, mineralocorticoid; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.115.06709
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Mineralocorticoid receptor (MR) antagonists slow down the progression of heart failure after myocardial infarction (MI), but the cell-specific role of MR in these benefits is unclear. In this study, the role of MR expressed in vascular smooth muscle cells (VSMCs) was investigated. Two months after coronary artery ligation causing MI, mice with VSMC-specific MR deletion (MI-MR SMKO ) and mice treated with the MR antagonist finerenone (MI-fine) had improved left ventricular compliance and elastance when compared with infarcted control mice (MI-CTL), as well as reduced interstitial fibrosis. Importantly, the coronary reserve assessed by magnetic resonance imaging was preserved (difference in myocardial perfusion before and after induction of vasodilatation, mL mg −1 min −1 : MI-CTL: 1.1±0.5, nonsignificant; MI-MR SMKO : 4.6±1.6 [ P <0.05]; MI-fine: 3.6±0.7 [ P <0.01]). The endothelial function, tested on isolated septal coronary arteries by analyzing the acetylcholine-induced nitric oxide-dependent relaxation, was also improved by MR deletion in VSMCs or by finerenone treatment (relaxation %: MI-CTL: 36±5, MI-MR SMKO : 54±3, and MI-fine: 76±4; P <0.05). Such impairment of the coronary endothelial function on MI involved an oxidative stress that was reduced when MR was deleted in VSMCs or by finerenone treatment. Moreover, short-term incubation of coronary arteries isolated from noninfarcted animals with low-dose angiotensin-II (10 −9 mol/L) induced oxidative stress and impaired acetylcholine-induced relaxation in CTL but neither in MR SMKO nor in mice pretreated with finerenone. In conclusion, deletion of MR in VSMCs improved left ventricular dysfunction after MI, likely through maintenance of the coronary reserve and improvement of coronary endothelial function. MR blockage by finerenone had similar effects. Abstract : Supplemental Digital Content is available in the text.