Intern
    Workgroup Kuhn

    Heart

    Local Cardiac Functions of the NP/GC-A System counteract cardiac hypertrophy and fibrosis

    Michael Klaiber, Beatrice Dankworth, Teresa Fasig, Katharina Völker, Michaela Kuhn

    During chronic hemodynamic overload, the expression levels of ANP and especially BNP in the cardiac ventricles significantly increase. In vitro studies suggested that NPs in this situation may act not only as circulating endocrine factors but also as local antihypertrophic (ANP) and antifibrotic (BNP) cardiac factors. Indeed, our studies in genetic mouse models together support an important autocrine/paracrine role for the ANP-BNP-GC-A signaling pathway, which moderates myocyte growth and extracellular matrix production in response to pressure overload or growth hormones such as Angiotensin II.

    Fluorometric recordings of intracellular Ca2+i-transients in isolated adult cardiomyocytes together with biochemical analyses indicate that cGMP-dependent protein kinase I (PKG I) is the downstream target activated by the ANP/GC-A/cGMP-signalling pathway in cardiac myocytes. cGMP/PKG I-mediated modulation of regulator of G-protein signalling (RGS) 2 and subsequent inhibition of AT1/Gαq-signalling appear to mediate the specific counterregulation of the calcium-responses of myocytes to Angiotensin II by ANP.

    The stimulatory effects of Angiotensin II (Ang II) on cardiac myocyte calcium handling are mediated by transient receptor potential canonical (TRPC3/C6) channels. ANP inhibits these calcium-responses by GC-A/cGMP-dependent activation of cGMP-dependent protein kinase I (PKG I) and phosphorylation / activation of regulator of G-protein signalling (RGS) 2. Thereby ANP locally counteracts the cardiac hypertrophic responses to Ang II.

    In our ongoing research projects in Sonderforschungsbereich SFB 487 and IZKF E-119 and E-163 we are elucidating how ANP and BNP and their GC-A receptor influence growth and mechanical functions of cardiac myocytes and their crosstalk with neighboring endothelia. In particular we try to dissect the specific postreceptor pathways mediating opposite actions of the same ligand-receptor system in cardiomyocytes (inhibition of growth) and endothelia (stimulation of proliferation).

    Reference List

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    Kuhn M, Holtwick R, Baba HA, Perriard J-C, Schmitz W, Ehler E (2002) Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice. Heart 87:368-374.

    Holtwick R, Baba HA, Pierkes M, Gehrmann J, Risse D, Kuhn M (2002) Left but not right cardiac hypertrophy in ANP-receptor deficient mice is prevented by AT1 receptor antagonist losartan. J Cardiovasc Pharmacol 40:725-734.

    Holtwick R, Van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, Kuhn M (2003) Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest 111:1399-1407.

    See accompanying Editorial by Molkentin JD. J Clin Invest 2003;111:1275-7

    Wollert K.C., Begrow F, Kilic A, Yurukova S, Gambaryan S, Walter U, Lohmann S, Kuhn M (2003) Increased effects of C-type natriuretic peptide on contractility and calcium handling in hearts of mice overexpressing cyclic GMP - dependent Protein Kinase I. Br J Pharmacol 140: 1227–1236.

    Kirchhof P, Fabritz L, Kilic A, Begrow F, Breithardt G, Kuhn M (2004) Ventricular arrhythmias, increased cardiac calmodulin kinase II expression, and altered repolarization kinetics in ANP receptor deficient mice. J Mol Cell Cardiol 36:691-700.

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    Kliche K, Kuhn M, Hillebrand U, Ludwig Y, Stock C, Oberleithner H (2006) Direct aldosterone action on mouse cardiomyocytes detected with atomic force microscopy. Cell Physiol Biochem 18:265-274.

    Yurukova S, Kilic A, Völker K, Leineweber K, Dybkova N, Maier LS, Brodde O-E, Kuhn M (2007) CamKII – mediated increased lusitropic responses to ß-adrenoreceptor stimulation in ANP – receptor deficient mice. Cardiovasc Res 73(4):678-688.

    Kilic A, Bubikat, A, Gaßner B, Baba H.A., Kuhn M. (2007) Local actions of atrial natriuretic peptide counteract angiotensin II stimulated cardiac remodeling. Endocrinology 148:4162-4169.
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    Klaiber M, Kruse M, Völker K, Schröter J, Feil R, Freichel M, Gerling A, Feil S, Dietrich A, Londoño JE, Baba HA, Abramowitz J, Birnbaumer L, Penninger JM, Pongs O, Kuhn M. (2010) Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2. Basic Res Cardiol 105:583-595.

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