Lack of NO-GC in periostin ⁺ myofibroblasts amplifies cardiac remodeling following Ang II infusion

Myocardial fibrosis is triggered, among other pathologies, by hypertension in conjunction with high angiotensin II (Ang II) levels. It is defined by excessive deposition of extracellular matrix (ECM) proteins such as collagen and by the expression of matricellular proteins such as periostin (Postn). Cardiac myofibroblasts (CMF), a highly proliferative and secretory cell type not found in healthy hearts, are believed to be the main source of ECM proteins. As a result, CMF contribute to increased muscle stiffness, an important feature of fibrosis, to heart failure progression and mortality. The nitric oxide (NO)/cGMP pathway is thought to have anti-fibrotic effects in the heart, but the role of this cascade in CMF is poorly understood.

We generated PostniCre-based CMF-specific NO-GC knockout (cKO) and littermate control (CTR) mice and subjected them to an Ang II-induced model of cardiac fibrosis. Compared to CTR, deficiency of NO-GC in CMFs resulted in increased myocardial collagen deposition and a larger cross-sectional area of cardiomyocytes. In addition, non-invasive echocardiography revealed global abnormalities in cardiac structure and function, i.e. a decrease in ejection fraction and fractional shortening, as well as local changes in muscle deformation in the cKO. Compared to CTR, CMFs from Ang II-treated cKO hearts showed an accelerated proliferation rate, which was reversed by 8-Br-cGMP. Interestingly, neither CMF stiffness nor cell migration or intracellular Ca2+ signals were dependent on the NO-GC status.

To conclude, endogenous NO-GC activity limits both the secretory and proliferative behavior of CMF and thus the extent of Ang II-induced myocardial damage and dysfunction.