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ETHNOPHARMACOLOGICAL RELEVANCE Si-Miao-Yong-An decoction (SMYAD) is a traditional Chinese herbal formulation. SMYAD first appeared in the Eastern Han Dynasty according to the "Shen Yi Mi Zhuan". Then the formula was recorded in the "Yan Fang Xin Bian" edited by medical scientist Bao Xiangao in the Qing Dynasty. This well-known prescription has been traditionally used for gangrene and vascular vasculitis. It is mainly used for cardiovascular and endocrine diseases in current clinical applications and research. AIM OF STUDY In this study, the role and underlying mechanisms of SMYAD against cardiac hypertrophy and fibrosis in the β-adrenoceptor agonist isoprenaline induced heart failure model were investigated. MATERIALS AND METHODS The heart failure animal model was established via injected isoprenaline in rats. Cardiac structure and function were evaluated by echocardiography. HE staining and Masson's trichrome staining were employed to evaluate myocardial tissue morphology. The serum biochemical indexes were measured by biochemical kits. BNP was tested by ELISA kit. Expression of mRNA was evaluated with real-time PCR. Cardiomyocyte morphology was assessed by immunofluorescence. Phosphorylated and total p38 MAPK, Akt were analyzed by Western blot. Generation of reactive oxygen species (ROS) generation was evaluated by CM-H2DCFDA fluorescent staining. Formula identification of chemical constituents of SMYAD in plasma was detected through liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS SMYAD improved the cardiac function in ISO induced heart failure rat model via protecting rat from developing cardiac hypertrophy and fibrosis. SMYAD also decreased plasma expression of these biochemical indexes. It was found that SMYAD could regulate cardiac hypertrophy and fibrosis makers' mRNA levels in vitro and vivo. In addition, SMYAD inhibited the phosphorylation of p38 MAPK and Akt, which are important mediators in the pathogenesis of isoprenaline-induced cardiac hypertrophy and fibrosis. It also showed that the components of SMYAD in rat plasma exerted myocardial cell protective activity. CONCLUSION In sum, SMYAD comprise more than one active ingredient to the pursuit of combination therapies instead of specifically target a single disease-causing molecule. These findings suggest that SMYAD is a potential pharmacological candidate for the treatment of cardiac hypertrophy and fibrosis, induced by β-adrenoceptor agonists.