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Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants

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Abstract

Stimulators of the soluble guanylyl cyclase (sGC) are emerging therapeutic agents in cardiovascular diseases. Genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease. Studies investigating sGC stimulators in subjects with CAD and carrying risk-related variants in sGC are, however, lacking. Here, we functionally investigate the impact of coding GUCY1A3 variants on sGC activity and the therapeutic potential of sGC stimulators in vitro. In addition to a known loss-of-function variant, eight coding variants in GUCY1A3 were cloned and expressed in HEK 293 cells. Protein levels and dimerization capability with the β1 subunit were analysed by immunoblotting and co-immunoprecipitation, respectively. All α1 variants found in MI patients dimerized with the β1 subunit. Protein levels were reduced by 72 % in one variant (p < 0.01). Enzymatic activity was analysed using cGMP radioimmunoassay after stimulation with a nitric oxide (NO) donor. Five variants displayed decreased cGMP production upon NO stimulation (p < 0.001). The addition of the sGC stimulator BAY 41-2272 increased cGMP formation in all of these variants (p < 0.01). Except for the variant leading to decreased protein level, cGMP amounts reached the wildtype NO-induced level after addition of BAY 41-2272. In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a sGC stimulator in vitro. These results might therefore represent the starting point for discovery of novel treatment strategies for patients at risk with coding GUCY1A3 variants.

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Acknowledgments

The authors thank Ann-Marie Kahlert and Laura Schwab for technical assistance. This work has been funded by the Deutsche Forschungsgemeinschaft (DFG) as part of the Sonderforschungsbereich CRC 1123 (B02). This study was also supported by Grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, Grant 01ZX1313A-2014), and the European Union Seventh Framework Programme FP7/2007-2013 under Grant agreement No. HEALTH-F2-2013-601456 (CVgenes-at-target). T.K. was supported by a rotation Grant from the German Centre for Cardiovascular Research (DZHK).

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Authors and Affiliations

  1. Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany

    Jana Wobst, Simon von Ameln, Bernhard Wolf, Tan An Dang, Hendrik B. Sager, Christian Hengstenberg, Heribert Schunkert & Thorsten Kessler

  2. Department of Proteomics and Signal Transduction, Max-Planck-Institut für Biochemie, Am Klopferspitz 18, 82152, Martinsried, Germany

    Michael Wierer

  3. Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Maria-Goeppert-Str. 1, 23562, Lübeck, Germany

    Stephanie Tennstedt & Jeanette Erdmann

  4. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., Partner Site Munich Heart Alliance, 80636, Munich, Germany

    Christian Hengstenberg & Heribert Schunkert

  5. Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Medizinische Fakultät MA N1/39, 44780, Bochum, Germany

    Doris Koesling

  6. Physiologisches Institut, Julius-Maximilians-Universität Würzburg, Röntgenring 9, 97070, Würzburg, Germany

    Andreas Friebe

  7. Institut für Laboratoriumsmedizin, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany

    Siegmund L. Braun

  8. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) e.V., Partner Site Hamburg/Kiel/Lübeck, 23562, Lübeck, Germany

    Jeanette Erdmann

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  1. Jana Wobst
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Wobst, J., von Ameln, S., Wolf, B. et al. Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants. Basic Res Cardiol 111, 51 (2016). https://doi.org/10.1007/s00395-016-0570-5

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