Urotensin II Induces Cardiac Fibrosis through the TGF-β/Smad Signaling Pathway during the Development of Cardiac Hypertrophy

Abstract

Myocardial fibrosis is an important pathological phenomenon of cardiac remodeling that is induced by hypertension, myocardial ischemia, valvular heart disease, hypertrophic cardiomyopathy, and other heart diseases and can progress to heart failure. Urotensin II (UII) is regarded as a cardiovascular autacoid/hormone that is not only the most potent vasoconstrictor in mammals but also involved in cardiac remodeling. However, the molecular mechanisms responsible for UII-induced cardiac fibrosis have not yet been fully elucidated. Therefore, we aimed to investigate the effect of UII on myocardial fibrosis in cardiac hypertrophy and the mechanism of UII-induced cardiac fibrosis. Cardiac tissue from mice subjected to Transverse aortic constriction (TAC) was collected. Cardiac hypertrophy, myocardial fibrosis, and the expression of UII protein were assessed using echocardiography and pathological and molecular biological analyses. The effect of UII on fibrosis was evaluated in UII-treated mice and isolated rat primary cardiac fibroblasts, and the results indicated that UII induced significant myocardial fibrosis and increases in the proliferation and fibrotic responses both in mice and cultured fibroblasts. Mechanistically, UII treatment induced activation of the TGF-β/Smad signaling pathway, which was suppressed by the UII receptor antagonist. In conclusion, UII plays critical roles in cardiac fibrosis by modulating the TGF-β/Smads signaling pathway, which may be a promising therapeutic target in hypertrophic cardiomyopathy and related problems, such as cardiac remodeling and heart failure.