NO-induced cGMP in cardiac function and remodelling

• Applicant: Privatdozent Dr. Michael Russwurm
• Subject Area: Pharmacology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452709061

The intracellular signalling molecule cGMP is generated in response to either nitric oxide (NO) or natriuretic peptides. In the heart, the function of NO-induced cGMP is highly controversial and NO-induced cGMP in adult cardiac myocytes remained barely if at all detectable. Recently, we have been able to demonstrate that NO-induced cGMP formed in cardiac fibroblasts enters cardiac myocytes through gap junctions in co-cultures. Here, we aim to demonstrate that gap junction-mediated transfer of NO-dependent cGMP occurs in native cardiac tissue and to unambiguously identify the cells generating this cGMP by lineage tracing in e. g. Tcf-21-positive fibroblasts. Furthermore, the physiological consequences of NO-induced cGMP in cardiac myocytes and Tcf-21-positive fibroblasts will be addressed. According to our previous findings in global NO-GC1 deficient mice, we aim to elucidate an antifibrotic action of NO-GC in Tcf-21 fibroblasts on Angiotensin II-induced cardiac fibrosis in vivo and monitor a possible upregulation of NO-GC. Moreover, the molecular mechanism underlying cGMP’s antifibrotic properties will be investigated in isolated, Tcf-21-positive fibroblasts.

• DFG Programme: Research Grants