Tanshinone IIA Stimulates Cystathionine γ-Lyase Expression and Protects Endothelial Cells from Oxidative Injury

Tanshinone IIA (Tan IIA), an active ingredient of Danshen, is a well-used drug to treat cardiovascular diseases. Currently, the mechanisms involved remain poorly understood. Given that many actions of Tan IIA could be similarly achieved by hydrogen sulfide (H₂S), we speculated that Tan IIA might work through the induction of endogenous H₂S. This study was to test this hypothesis. Exposure to endothelial cells to Tan IIA elevated H₂S-synthesizing enzyme cystathionine γ-Lyase (CSE), associated with an increased level of endogenous H₂S and free thiol activity. Further analysis revealed that this effect of Tan IIA was mediated by an estrogen receptor (ER) and cAMP signaling pathway. It stimulated VASP and CREB phosphorylation. Inhibition of ER or PKA abolished the CSE-elevating effect, whereas activation of ER or PKA mimicked the effect of Tan IIA. In an oxidative endothelial cell injury model, Tan IIA potently attenuated oxidative stress and inhibited cell death. In support of a role of endogenous H₂S, inhibition of CSE aggerated oxidative cell injury. On the contrary, supplement of H₂S attenuated cell injury. Collectively, our study characterized endogenous H₂S as a novel mediator underlying the pharmacological actions of Tan IIA. Given the multifaceted functions of H₂S, the H₂S-stimulating property of Tan IIA could be exploited for treating many diseases.