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Cardiac fibrosis is a common pathological progress of cardiovascular diseases results from the excessive accumulation of extracellular matrix(ECM). Previous studies showed that transforming growth factor(TGF)-β/Smad pathway is a canonical signaling pathway which can directly induce ECM gene expression. Qishen Granule (QSG), a traditional Chinese formula for heart failure (HF), has been proved definite therapeutic effects on cardiac fibrosis. While, its underlying mechanism remains unclear. This study aims to investigate the ability of QSG treatment to inhibit cardiac fibrosis in rats by acting on TGF-β and its downstream mediators such as Smad3 and GSK3β.
Male Sprague-Dawley (SD) rats were randomly divided into 4 groups: sham group (left anterior descending (LAD) artery ligation but without actual tying), model group (LAD ligation), QSG group (LAD ligation and treated with QSG), and Fosinopril group (LAD ligation and treated with fosinopril). The treatments were taken for a 28-day period, and 2D echocardiography was adopted at the end to evaluate the heart function. The degree of cardiac fibrosis was assessed by Hematoxylin-Eosin (HE), Masson's trichrome and picrosirius red staining. Collagen (I, III) content was assessed by the immunohistochemical method. mRNA and protein expression in TGF-β/Smad3 signaling pathway and its related mediators were detected by Real-Time PCR and Western blot respectively. Statistical analyses for the experimental data were performed by the IBM SPSS Statistics 20 software.
28 days after the surgery, the ejection fraction (EF) and fractional shortening (FS) values showed a marked decrease, while the left ventricular end-diastolic (LVEDd) and left ventricular end-systolic (LVEDs) dimension values increase for the model group, which indicates the induction of HF. Pathological staining showed significant changes of fibrosis in heart sections among different groups. Immunohistochemistry showed that the content of collagen I and III was dramatically increasing for the model group (vs the sham group) while was decreasing for the treatment groups (vs the model group). mRNA and protein levels of TGF-β, Smad3 and GSK3β between model and treatment group were significantly different, which suggests that the QSG may attenuate cardiac fibrosis through inhibiting TGF-β/Smad3 pathway and phosphorylation of GSK3β.
QSG has the efficacy to improve cardiac functions through inhibiting excess cardiac fibrosis. Its anti-fibrotic effects are probably related to the inhibition of the TGF-β/Smad3 pathway and the phosphorylation of GSK3β.