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Salvia miltiorrhiza Bge. (Danshen) is widely used to improve blood circulation and the dredge meridian in traditional Chinese medicine. In the present study, we evaluated the effects of dihydrotanshinone I (DHTS), a natural product from Danshen, on chronic high-fat feeding-induced cardiac remodeling and dysfunction. DHTS (25 mg/kg, intraperitoneal) did not affect blood glucose, insulin levels, and glucose intolerance. However, it alleviated diastolic dysfunction induced by the high-fat diet, as indicated by the increase in the ratio of peak early filling velocity to peak late filling velocity of the mitral and suppression of the extension of the isovolumic relaxation phase of the left ventricle. Further investigations revealed that DHTS ameliorated high-fat induced cardiac hypertrophy in mice and suppressed insulin-induced enlargement of cardiomyocytes in vitro. In neonatal cardiomyocytes, DHTS restored insulin-induced suppression of CCAAT/enhancer-binding protein beta-2 isoform (CEBPβ) and the phosphorylation of glycogen synthase kinase-3β (GSK3β) and extracellular signal-regulated kinase (ERK). Taken together, our results indicated that DHTS ameliorated cardiac hypertrophy and diastolic dysfunction in high-fat-fed mice, probably through the inhibition of insulin-induced suppression of CEBPβ and phosphorylation of GSK3β and ERK in cardiomyocytes. more...