Yan Qiaojing, Mao Zhimin, Hong Jingru, Gao Kun, Niimi Manabu, Mitsui Takahiko, Yao Jian
Division of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo 409-3898, Japan.
Division of Molecular Pathology, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo 409-3898, Japan.
Antioxidants (Basel). 2021 Jun 23;10(7):1007. doi: 10.3390/antiox10071007.
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 (HS), we speculated that Tan IIA might work through the induction of endogenous HS. This study was to test this hypothesis. Exposure to endothelial cells to Tan IIA elevated HS-synthesizing enzyme cystathionine γ-Lyase (CSE), associated with an increased level of endogenous HS 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 HS, inhibition of CSE aggerated oxidative cell injury. On the contrary, supplement of HS attenuated cell injury. Collectively, our study characterized endogenous HS as a novel mediator underlying the pharmacological actions of Tan IIA. Given the multifaceted functions of HS, the HS-stimulating property of Tan IIA could be exploited for treating many diseases.
丹参酮IIA（Tan IIA）是丹参的一种活性成分，是一种常用于治疗心血管疾病的药物。目前，其作用机制仍知之甚少。鉴于Tan IIA的许多作用可通过硫化氢（HS）类似地实现，我们推测Tan IIA可能通过诱导内源性HS发挥作用。本研究旨在验证这一假设。将内皮细胞暴露于Tan IIA可提高HS合成酶胱硫醚γ-裂解酶（CSE）的水平，同时内源性HS水平和游离巯基活性增加。进一步分析表明，Tan IIA的这种作用是由雌激素受体（ER）和cAMP信号通路介导的。它刺激了VASP和CREB的磷酸化。抑制ER或PKA可消除CSE升高的作用，而激活ER或PKA则可模拟Tan IIA的作用。在氧化型内皮细胞损伤模型中，Tan IIA可有效减轻氧化应激并抑制细胞死亡。为支持内源性HS的作用，抑制CSE会加剧氧化细胞损伤。相反，补充HS可减轻细胞损伤。总体而言，我们的研究将内源性HS确定为Tan IIA药理作用的一种新型介质。鉴于HS的多方面功能，Tan IIA的HS刺激特性可用于治疗多种疾病。
