title: Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction.
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.
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gueret
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Najah
authors.initials: N
authors.lastname: Harouki
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Julie
authors.initials: J
authors.lastname: Favre
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Galmiche
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Lionel
authors.initials: L
authors.lastname: Nicol
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Henry
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Marie
authors.initials: M
authors.lastname: Besnier
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jaisser
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.). antoine.ouvrard-pascaud@univ-rouen.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Ouvrard-Pascaud
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D006334:Heart Function Tests; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications* / Q000175:diagnosis; D009287:Naphthyridines / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D018161:Receptors, Mineralocorticoid / Q000187:drug effects; D012016:Reference Values; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D009287:Naphthyridines; D018161:Receptors, Mineralocorticoid; C576501:finerenone; D009569:Nitric Oxide
keywords: coronary vessels; myocardial infarction; receptors, mineralocorticoid