Activation of TGF‐β mediated SMAD pathway induces cardiac fibrosis in mice carrying targeted disruption of guanylyl cyclase/natriuretic peptide receptor‐A gene (547.17)

Mice carrying targeted‐disruption of the natriuretic peptide receptor‐A (GC‐A/NPRA) gene ( Npr1 ) have demonstrated cardiac hypertrophy with increased collagen deposition and fibrosis. The objective of this study was to determine the mechanisms regulating the development of fibrosis in Npr1 gene‐disrupted mice hearts. The Npr1 null mutant (Npr1 ‐/‐ , 0‐copy), heterozygous (Npr1 +/‐ , 1‐copy), and wild‐type (Npr1 +/+ , 2‐copy) mice were orally administered with transforming growth factor‐β1 receptor inhibitor GW788388 (2 mg/kg/day) for 28 days, and the hearts were isolated and used for quantification of fibrotic markers using real time quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) and Western blot analyses. Npr1 ‐/‐ null mutant mice showed 6‐fold induction of fibrosis in the hearts compared to wild‐type controls. Moreover, the expression of fibrotic markers such as connective tissue growth factor (CTGF), α‐smooth muscle actin (α‐SMA) and TGF‐βRI, TGF‐βRII and SMAD proteins were upregulated in Npr1 ‐/‐ mice hearts compared with age‐matched wild‐type controls. Whereas, treatment with TGF‐β inhibitor, GW788388, significantly prevented the cardiac fibrosis and potentially down‐regulated the expression of fibrotic markers and SMAD proteins in Npr1 ‐/‐ mice hearts. The results of the present study suggest that, induction of cardiac fibrosis in Npr1 ‐/‐ gene‐disrupted mice is majorly through TGF‐β mediated SMAD‐dependent pathway. Grant Funding Source : NIH