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Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification

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Abstract

In isolated cells, soluble guanylyl cyclase (sGC) activity is regulated by exogenous nitric oxide (NO) via downregulation of expression and posttranslational S-nitrosylation. The aim of this study was to investigate whether such regulatory mechanism impact on endothelium-dependent vasodilation in a newly developed mouse strain carrying an endothelial-specific overexpression of eNOS (eNOS++). When compared with transgene negative controls (eNOSn), eNOS++-mice showed a 3.3-fold higher endothelial-specific aortic eNOS expression, increased vascular cGMP and VASP phosphorylation, a L-nitroarginine (L-NA)-inhibitable decrease in systolic blood pressure, but normal levels of peroxynitrite and nitrotyrosine formation, endothelium-dependent aortic vasodilation and vasodilation to NO donors. Western blot analysis for sGC showed similar protein levels of sGC-α1 and sGC-β1 subunits in eNOSn and eNOS++. In striking contrast, the activity of isolated sGC was strongly decreased in lungs of eNOS++. Semiquantitative evaluation of sGC-β1-S-nitrosylation demonstrated that this loss of sGC activity is associated with increased nitrosylation of the enzyme in eNOS++, a difference that disappeared after L-NA-treatment. Our data suggest the existence of a physiologic NO-dependent posttranslational regulation of vascular sGC in mammals involving S-nitrosylation as a key mechanism. Because this mechanism can compensate for reduction in vascular NO bioavailability, it may mask the development of endothelial dysfunction.

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Acknowledgments

This study was supported by the Forschungskommission of the Heinrich-Heine-Universität Düsseldorf (Project 9772 109 to G.K., and project 9772 345 to T.S.).

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None declared.

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Authors and Affiliations

  1. Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Moorenstr. 5, 40225, Düsseldorf, Germany

    Marc Oppermann, Tatsiana Suvorava, Till Freudenberger, Vu Thao-Vi Dao, Jens W. Fischer & Georg Kojda

  2. Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA

    Martina Weber

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  1. Marc Oppermann
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  2. Tatsiana Suvorava
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  3. Till Freudenberger
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Correspondence to Georg Kojda.

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M. Oppermann and T. Suvorava contributed equally to this work.

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Oppermann, M., Suvorava, T., Freudenberger, T. et al. Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification. Basic Res Cardiol 106, 539–549 (2011). https://doi.org/10.1007/s00395-011-0160-5

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