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

• Published in: British journal of pharmacology 2019-12, Vol.176 (24), p.4696-4707
• Main Authors: Menges, Lukas, Krawutschke, Christian, Füchtbauer, Ernst‐Martin, Füchtbauer, Annette, Sandner, Peter, Koesling, Doris, Russwurm, Michael
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Coculture Techniques; Cyclic GMP - genetics; Cyclic GMP - metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gap Junctions - drug effects; Gap Junctions - metabolism; Gene Knock-In Techniques; Mice; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Nitric Oxide - pharmacology; Research Paper; Research Papers
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14835

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.