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The ANP/cGMP/cGMP-dependent protein kinase pathway counteracts Angiotensin II-stimulated calcium mobilization in cardiac myocytes

Background

The cardiac hormone atrial natriuretic peptide (ANP) exerts local, Guanylyl Cyclase-A (GC-A) – mediated myocardial effects to antagonize the Ca2+i-dependent hypertrophic growth response to Angiotensin II (Ang II). The present study aimed to characterize the specific molecular mechanisms mediating the reciprocal interactions between the ANP/GC-A and the Ang II/AT1 systems in the heart.

Results

Ca2+i-transients and cell shortening were monitored in Indo-1 loaded isolated, electrically paced adult murine cardiomyocytes. Ang II (1–100 nM) acutely enhanced the amplitude of Ca2+i-transients, accelerated Ca2+i-decay and stimulated cell shortening. These effects were completely prevented by ANP (100 nM). In contrast, the myocyte calcium responses to β-adrenergic stimulation (10 nM isoprenaline) were not affected by ANP. To study the role of cGMP-dependent protein kinase I (PKG I), we evaluated the ANP effects on calcium regulation in myocytes from transgenic mice with cardiac deletion of PKG I. The inhibitory effects of ANP on Ang II signaling were totally abolished in PKG I-deficient myocytes. Rp-8-pCPT-cGMPs, a membrane-permeable PKG inhibitor, mimicked the effects of genetic PKG I deletion. One downstream target of PKG I in the heart is regulator of G-protein signaling (RGS)-2, which attenuates Ang II – Gαq protein signaling. In RGS2 – deficient myocytes Ang II – induced Ca2+i-mobilization was enhanced. Moreover, the inhibitory effect of ANP was totally abolished.

Conclusion

Taken together, our data indicate that PKG I is a downstream target activated by the ANP/GC-A/cGMP-signaling pathway in cardiac myocytes. cGMP/PKG I-stimulated phosphorylation of RGS2 and subsequent inhibition of AT1/Gq-signaling appear to mediate the counterregulation of the cardiac effects of Ang II by ANP.

Acknowledgements

Supported by Sonderforschungbereich SFB 487

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Correspondence to Michael Klaiber.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Klaiber, M., Völker, K., Gaßner, B. et al. The ANP/cGMP/cGMP-dependent protein kinase pathway counteracts Angiotensin II-stimulated calcium mobilization in cardiac myocytes. BMC Pharmacol 9, P34 (2009). https://doi.org/10.1186/1471-2210-9-S1-P34

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Keywords

  • Cardiac Myocytes
  • Atrial Natriuretic Peptide
  • Hypertrophic Growth
  • Specific Molecular Mechanism
  • Cardiac Hormone