Abstract:
The present work focused on the investigation of the putative role of the cGMP-dependent protein kinase I (cGKI) in Postn+ cardiac myofibroblasts (CMFs) in mediating the well-known antifibrotic actions of the NO/cGMP and NP/cGMP signaling cascade(s). To address this question, we generated mice with a specific deletion of cGKI in CMFs (cmfKO) and corresponding littermate control animals (CTR) by using a transgenic PostniCreTg/+ mouse line expressing the tamoxifen (TAM)-inducible Cre recombinase controlled by the Postn-Promotor (Kaur et al., 2016). To induce cardiac remodeling, osmotic minipumps releasing angiotensin II (Ang II) over 28 days were implanted subcutaneously. CMF-specific Cre-recombination resulted in a pronounced reduction of cGKI expression levels in fibrotic heart areas as well as in primary cardiac fibroblasts (CF)/CMF cell cultures derived from TAM and Ang II-treated cmfKO mice. Interestingly, although both genotypes responded identically to Ang II in terms of blood pressure and heart weight, cmfKO mice exhibited a slightly increased myocardial vulnerability compared to Ang II-treated CTR animals. In line with this adverse outcome, Ang II challenged cmfKO mice displayed a significantly increased collagen deposition as well as cardiomyocyte (CM) cross sectional areas and cell death versus corresponding CTR animals. Furthermore, cmfKO mice showed a structure-related decline in global cardiac performance (%EF, %FS) and muscle deformation capacity following prolonged Ang II stimulation compared to corresponding CTR mice. Consistent with the observed phenotype in vivo, primary CF/CMFs isolated from Ang II-treated cmfKO mice exhibited accelerated proliferation behavior compared with CTR-derived CF/CMFs. Future studies are still required to address how cGKI contributes to further CMF characteristics including ECM-production and migration. Overall, the present work provides evidence for a cardioprotective role of the cGMP/cGKI cascade in CMF during Ang II-mediated cardiac remodeling, with these antifibrotic effects attributable to tight regulation of CMF expansion.
cGMP