Tanshinone VI Attenuates the Development of Heart Failure with Preserved Ejection Fraction in Mice

Treatments to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) are urgently needed. Tanshinone VI (TanVI) is a compound extracted from the roots of Salvia miltiorrhiza Bunge (Lamiaceae) that exerts inhibitory effects on the development of cardiac remodeling under experimental conditions. However, the therapeutic effects of TanVI on HFpEF remain unclear. The present study aims to investigate the therapeutic effects of TanVI in a mouse model of HFpEF. HFpEF mice were prepared by feeding C57BL/6N mice a high-fat diet and providing water containing N^[ω]-nitro-L-arginine methyl ester hydrochloride (L-NAME) for 15 weeks, and TanVI (3 mg/kg/d) or vehicle was administered intraperitoneally using an osmotic pump for 5 weeks until the end of the experiment. The administration of a high-fat diet and L-NAME resulted in cardiac diastolic dysfunction with cardiac hypertrophy and fibrosis. In contrast, treatment with TanVI markedly attenuated cardiac hypertrophy and fibrosis and prevented cardiac diastolic dysfunction. In HFpEF mouse hearts, the phosphorylation levels of mitogen-activated protein (MAP) kinases such as c-Raf, MEK1/2, and extracellular signal-regulated kinase 1/2 (ERK1/2), which regulate cardiac hypertrophy and fibrosis, were elevated. In contrast, treatment with TanVI reversed the phosphorylation levels of c-Raf, MEK1/2, and ERK1/2. The present study showed that TanVI prevented the development of HFpEF by reducing cardiac remodeling. Furthermore, our findings suggest, at least in part, that TanVI attenuates the development of HFpEF by inhibiting the MAP kinase signaling pathway.