0316 : Vascular smooth muscle mineralocorticoid receptor contributes to coronary and left ventricular dysfunction after myocardial infarction

Abstract

Because mineralocorticoid receptor (MR) antagonists have shown efficacy in slowing down the progression of heart failure after myocardial infarction (MI), there is interest to elucidate the cell-specific involvement of MR. Indeed, the role of MR in vascular smooth muscle cells (VSMC) in heart failure, especially its impact on coronary circulation, has never been investigated. Two months after MI, mice lacking the MR specifically in VSMC (MI-MRSMKO) and mice treated with the MR antagonist finerenone (MI-fine) had better coronary function than control (MI-CTL), as assessed by acetylcholine-induced relaxation of isolated arteries (relaxation %: MI-CTL: 36±5, MI-MRSMKO: 54±3, MI-fine: 76±4; P<0.05). Furthermore, MRI showed that the coronary reserve was increased (ml/mg/min: MI-CTL: 1.1±0.5, MIMRSMKO: 4.6±1.6, P<0.05; MI-fine: 3.6±0.7, P<0.01). Incubation with the NAPDH-oxidase inhibitor apocynin of coronary arteries improved acetylcholineinduced relaxation in MI-CTL to a higher extent than in MI-MRSMKO and MIfine mice, suggesting that MR antagonism reduces oxidative stress-mediated endothelial dysfunction. Indeed, incubation of coronary arteries from non-infarcted animals with 10-9M angiotensin II induced oxidative stress and impaired acetylcholine- induced relaxation in CTL mice, but not in MRSMKO or in 4 weeks finerenone-treated mice. These improvements in coronary function were accompanied in MI-MRSMKO mice by reduced LV fibrosis and improved LV function. After MI, VSMC-specific MR invalidation benefits LV dysfunction, likely through improvement of coronary reserve and of coronary endothelial function, demonstrating for the first time the deleterious role of smooth muscle MR activation in heart failure. Furthermore, systemic MR blockade by finerenone confers additional functional improvements.