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).
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