title: Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function.
abstract: Antagonists of the mineralocorticoid receptor improve morbidity and mortality in patients with severe heart failure. However, the cell types involved in these beneficial effects are only partially known. The aim of this work was to evaluate whether genetic deletion of mineralocorticoid receptors in mouse cardiomyocytes or fibroblasts in vivo is cardioprotective after chronic left ventricular pressure overload. After transverse aortic constriction, mice deficient in myocyte mineralocorticoid receptors but not those deficient in fibroblast mineralocorticoid receptors were protected from left ventricular dilatation and dysfunction. After pressure overload, left ventricular ejection fraction was significantly higher in mice lacking myocyte mineralocorticoid receptors (70.2±4.4%) as compared with control mice (54.3±2.5%; P<0.01). Myocyte mineralocorticoid receptor-deficient mice showed mild cardiac hypertrophy at baseline, contributing to reduced left ventricular wall tension at baseline and after pressure overload. Cardiac levels of phospho-extracellular signal-regulated kinase 1/2 were higher in myocyte mineralocorticoid receptor-deficient mice than in control mice after pressure overload. Neither fibroblast nor myocyte mineralocorticoid receptor ablation altered the development of cardiac hypertrophy or fibrosis after pressure overload. Both mineralocorticoid receptor mutant mouse strains developed similar degrees of myocyte apoptosis, proinflammatory gene expression, and macrophage infiltration after pressure overload. Thus, mineralocorticoid receptors in cardiac myocytes but not in fibroblasts protect from cardiac dilatation and failure after chronic pressure overload.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 29, 79104 Freiburg, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Lother
authors.forename: Stefan
authors.initials: S
authors.lastname: Berger
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.forename: Stephan
authors.initials: S
authors.lastname: Rösner
authors.forename: Andreas
authors.initials: A
authors.lastname: Ecke
authors.forename: Frederico
authors.initials: F
authors.lastname: Barreto
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018161:Receptors, Mineralocorticoid; D048049:Extracellular Signal-Regulated MAP Kinases