Atrial natriuretic peptide locally counteracts the deleterious effects of cardiomyocyte mineralocorticoid receptor activation.

• Material Type: 博士論文
• Title: Atrial natriuretic peptide locally counteracts the deleterious effects of cardiomyocyte mineralocorticoid receptor activation.
• Author/Editor: Nakagawa, Hitoshi; Oberwinkler, Heike; Nikolaev, Viacheslav O.; Gaßner, Birgit; Umbenhauer, Sandra; Wagner, Helga; Saito, Yoshihiko; Baba, Hideo A.; Frantz, Stefan; Kuhn, Michaela
• Author Heading: Nakagawa, Hitoshi; Oberwinkler, Heike; Nikolaev, Viacheslav O.; Gaßner, Birgit; Umbenhauer, Sandra; Wagner, Helga; Saito, Yoshihiko; Baba, Hideo A.; Frantz, Stefan; Kuhn, Michaela
• Publication, Distribution, etc.: American Heart Association / Lippincott Williams & Wilkins
• Publication Date: 2014-09
• Publication Date (W3CDTF): 2014-09
• Alternative Title: 心房ナトリウム利尿ペプチドは、ミネラルコルチコイド受容体活性を抑制して心筋リモデリングを予防する
• Periodical title: Circulation. Heart failure
• No. or year of volume/issue: 7 5
• Volume: 7
• Issue: 5
• Pages: 814-821
• ISSN (Periodical Title): ISSN : 1941-3289
• Degree grantor/type: 奈良県立医科大学
• Date Granted: 2015-03-16
• Dissertation Number: 甲第630号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: aldosterone; angiotensins; atrial natriuretic factor; heart failure
• Target Audience: 一般
• Note (General): type:Thesis; 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.METHODS AND 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.; 博士（医学）・甲第630号・平成27年3月16日; © 2014 American Heart Association, Inc.; identifier:Circulation. Heart failure Vol.7 No.5 p.814-821; identifier:19413289; identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/2960; identifier:Circulation. Heart failure, 7(5): 814-821
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.1161/CIRCHEARTFAILURE.113.000885
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU

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