Ursolic acid ameliorates oxidative stress, inflammation and fibrosis in diabetic cardiomyopathy rats

Diabetic cardiomyopathy is a major and severe cardiovascular complication of diabetes mellitus. Ursolic acid, a pentacyclic triterpene compound widespread in fruits and plants, performs a variety of pharmacological activities including lowering blood glucose, anti-oxidation, anti-inflammation and anti-fibrosis. Our present study aimed to investigate the cardioprotective effects of ursolic acid on diabetic cardiomyopathy rats and uncover its underlying mechanism. Diabetes mellitus was induced by a single injection of STZ-only (40 mg/kg, i.v.) in male SD rats. Animals were divided into three groups (n = 10): control group (normal saline, i.g.), diabetic group (normal saline, i.g.) and diabetic+ursolic acid group (35 mg/kg UA+ normal saline, i.g.). Rats were administered for 8 weeks from 5th to 12th week. After the last administration, cardiac function was evaluated; HWI was calculated; FBG, CK, LDH in serum and SOD, MDA in cardiac tissue were detected. HE staining and Masson trichrome staining were employed to observe pathological alterations. Immunohistochemistry and western blotting were taken to determine the expression levels of TNF-alpha, MCP-1, TGF-beta 1 and MMP-2 in the heart. The results dramatically showed increased levels of FBG, CK, LDH, MDA and a decreased activity of SOD in diabetic group, in which left ventricular dysfunction, cardiac myocytes hypertrophy, inflammatory cell infiltration and myocardial interstitial fibrosis had also been found. What's more, the expressions of TNF-a, MCP-1 and TGF-beta 1 were significantly up-regulated and the expression of MMP-2 was markedly down-regulated in myocardium. Interestingly, treatment with ursolic acid remarkably ameliorated these changes. Collectively, our study strongly showed that ursolic acid is capable of improving the cardiac structure and function in STZ-induced diabetic cardiomyopathy rats by attenuating oxidative stress, inflammation and fibrosis.