title: Atrial natriuretic peptide locally counteracts the deleterious effects of cardiomyocyte mineralocorticoid receptor activation.
abstract: BACKGROUND
  The endocrine balance between atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone system is critical for the maintenance of arterial blood pressure and volume homeostasis. This study investigated whether a cardiac imbalance between ANP and aldosterone, toward increased mineralocorticoid receptor (MR) signaling, contributes to adverse left ventricular remodeling in response to pressure overload.
  
  
  RESULTS
  We used the MR-selective antagonist eplerenone to test the role of MRs in mediating pressure overload-induced dilatative cardiomyopathy of mice with abolished local, cardiac ANP activity. In response to 21 days of transverse aortic constriction, mice with cardiomyocyte-restricted inactivation (knockout) of the ANP receptor (guanylyl cyclase [GC]-A) or the downstream cGMP-dependent protein kinase I developed enhanced left ventricular hypertrophy and fibrosis together with contractile dysfunction. Treatment with eplerenone (100 mg/kg/d) attenuated left ventricular hypertrophy and fully prevented fibrosis, dilatation, and failure. Transverse aortic constriction induced the cardiac expression of profibrotic connective tissue growth factor and attenuated the expression of SERCA2a (sarcoplasmic reticulum Ca(2+)-ATPase) in knockout mice, but not in controls. These genotype-dependent molecular changes were similarly prevented by eplerenone. ANP attenuated the aldosterone-induced nuclear translocation of MRs via GC-A/cGMP-dependent protein kinase I in transfected HEK 293 (human embryonic kidney) cells. Coimmunoprecipitation and fluorescence resonance energy transfer experiments demonstrated that a population of MRs were membrane associated in close interaction with GC-A and cGMP-dependent protein kinase I and, moreover, that aldosterone caused a conformational change of this membrane MR/GC-A protein complex which was prevented by ANP.
  
  
  CONCLUSIONS
  ANP counter-regulates cardiac MR activation in hypertensive heart disease. An imbalance in cardiac ANP/GC-A (inhibition) and aldosterone/MR signaling (augmentation) favors adverse cardiac remodeling in chronic pressure overload.
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Heike
authors.initials: H
authors.lastname: Oberwinkler
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Birgit
authors.initials: B
authors.lastname: Gaßner
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Umbenhauer
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Helga
authors.initials: H
authors.lastname: Wagner
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Frantz
authors.affiliation: From the Institute of Physiology (H.N., H.O., B.G., M.K.) and Comprehensive Heart Failure Center (H.N., S.F., M.K.), University Würzburg, Würzburg, Germany; Emmy Noether Group of the Deutsche Forschungsgemeinschaft, Department of Cardiology and Pneumology, University Göttingen, Göttingen, Germany (V.O.N.); Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany (S.U., H.W, S.F.); First Department of Internal Medicine, Nara Medical University, Kashihara, Japan (Y.S.); and Institute of Pathology, University Duisburg-Essen, Essen, Germany (H.A.B.). michaela.kuhn@mail.uni-wuerzburg.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D000077545:Eplerenone; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D055513:Connective Tissue Growth Factor; D013148:Spironolactone; D000077545:Eplerenone; D009320:Atrial Natriuretic Factor; D004247:DNA; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506950:Atp2a3 protein, mouse
keywords: aldosterone; angiotensins; atrial natriuretic factor; heart failure