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Mind the gap (junction): cGMP induced by nitric oxide in cardiac myocytes originates from cardiac fibroblasts

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DOI

  • Lukas Menges, Ruhr University Bochum
  • ,
  • Christian Krawutschke, Ruhr University Bochum
  • ,
  • Ernst Martin Füchtbauer
  • Annette Füchtbauer
  • Peter Sandner, Bayer AG
  • ,
  • Doris Koesling, Ruhr University Bochum
  • ,
  • Michael Russwurm, Ruhr University Bochum

Background and Purpose: The intracellular signalling molecule cGMP, formed by NO-sensitive GC (NO–GC), has an established function in the vascular system. Despite numerous reports about NO-induced cGMP effects in the heart, the underlying cGMP signals are poorly characterized. Experimental Approach: Therefore, we analysed cGMP signals in cardiac myocytes and fibroblasts isolated from knock-in mice expressing a FRET-based cGMP indicator. Key Results: Whereas in cardiac myocytes, none of the known NO–GC-activating substances (NO, GC activators, and GC stimulators) increased cGMP even in the presence of PDE inhibitors, they induced substantial cGMP increases in cardiac fibroblasts. As cardiac myocytes and fibroblasts are electrically connected via gap junctions, we asked whether cGMP can take the same route. Indeed, in cardiomyocytes co-cultured on cardiac fibroblasts, NO-induced cGMP signals were detectable, and two groups of unrelated gap junction inhibitors abolished these signals. Conclusion and Implication: We conclude that NO-induced cGMP formed in cardiac fibroblasts enters cardiac myocytes via gap junctions thereby turning cGMP into an intercellular signalling molecule. The findings shed new light on NO/cGMP signalling in the heart and will potentially broaden therapeutic opportunities for cardiac disease.

OriginalsprogEngelsk
TidsskriftBritish Journal of Pharmacology
Vol/bind176
Nummer24
Sider (fra-til)4696-4707
Antal sider12
ISSN0007-1188
DOI
StatusUdgivet - 1 dec. 2019

Bibliografisk note

Funding Information:
The authors gratefully acknowledge the technical assistance of Lisbeth Ahm Hansen, Lamija Kavazovic, and Ulla Krabbe. The contributions of Arkadius Pacha who started the cardiac myocyte preparation and of Caroline Vollmers who established the co-cultures are greatly appreciated. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KO 1157/4-1) and the Kommission f?r Finanzautonomie und Erg?nzungsmittel of the Medical Faculty (KOFFER).

Funding Information:
The authors gratefully acknowledge the technical assistance of Lisbeth Ahm Hansen, Lamija Kavazovic, and Ulla Krabbe. The contributions of Arkadius Pacha who started the cardiac myocyte preparation and of Caroline Vollmers who established the co‐cultures are greatly appreciated. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KO 1157/4‐1) and the Kommission für Finanzautonomie und Ergänzungsmittel of the Medical Faculty (KOFFER).

Publisher Copyright:
© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

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