丹参酮IIA通过激活DAXX/MEK/ERK1/2通路抑制阿霉素诱导的心脏毒性过程中的心肌细胞凋亡并挽救心脏功能。
Tanshinone IIA inhibits cardiomyocyte apoptosis and rescues cardiac function during doxorubicin-induced cardiotoxicity by activating the DAXX/MEK/ERK1/2 pathway.
作者信息
Xu Linhao, He Daqiang, Wu Yirong, Shen Lishui, Wang Yongmei, Xu Yizhou
机构信息
Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, #261 Huansha Road, Shangcheng District, Hangzhou, Zhejiang 310006, China; Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
出版信息
Phytomedicine. 2022 Dec;107:154471. doi: 10.1016/j.phymed.2022.154471. Epub 2022 Sep 21.
BACKGROUND
Heart failure (HF) is a common cardiovascular syndrome. Tanshinone IIA (Tan IIA) is a pharmacologically active monomer that exerts a significant cardioprotective effect in the clinic; however, the specific mechanisms are not fully understood.
PURPOSE
We mainly investigated the protective effects of Tan IIA on doxorubicin (DOX)-induced HF.
METHODS
In an in vitro study, H9C2 and HL-1 cells were cultured and treated with DOX and Tan IIA for 24 h, we investigated the mechanism underlying Tan IIA-mediated protection. In an in vivo study, a model of DOX-induced HF was established in C57BL/6 mice that were divided into the six groups randomly: a control group, a DOX group, DOX groups treated with Tan IIA (DOX+Tan IIA) at dosages of 2.5, 5 and 10 mg/kg/day and DOX groups treated with N-acetylcysteine (NAC) at dosages of 200 mg/kg/day.
RESULT
The results demonstrated that Tan IIA significantly increased cell viability and protected against DOX-induced apoptosis. RNA-sequencing showed that the genes expression associated with the apoptotic signaling pathway was altered by Tan IIA. Among the differentially expressed genes, death-domain associated protein (DAXX), which plays an critical role in apoptotic signaling, exhibited increased expression under Tan IIA treatment. In addition, RNA interference was used to silence the expression of DAXX, which abolished Tan IIA-mediated protection against DOX-induced apoptosis; this effect was associated with extracellular signal-regulated protein kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) expression. In the in vivo study, the echocardiography results revealed that heart function was rescued by Tan IIA, and the histomorphology results showed that Tan IIA prevented myocardial structural alteration and myofibril disruption. Furthermore, Tan IIA induced the expressions of DAXX, p-ERK1/2 and p-MEK. Tan IIA also inhibited apoptosis by suppressing the expression of cleaved caspase-8, p-P38 and cleaved caspase-3.
CONCLUSION
Our results provide novel interpretations into the important role of DAXX in DOX-induced cardiotoxicity and show that Tan IIA may be a novel agent strategy for HF treatment via activating the DAXX/MEK/ERK1/2 pathway.
背景
心力衰竭（HF）是一种常见的心血管综合征。丹参酮IIA（Tan IIA）是一种具有药理活性的单体，在临床上发挥着显著的心脏保护作用；然而，其具体机制尚未完全明确。
目的
我们主要研究了Tan IIA对阿霉素（DOX）诱导的HF的保护作用。
方法
在体外研究中，培养H9C2和HL-1细胞，并用DOX和Tan IIA处理24小时，我们研究了Tan IIA介导保护作用的潜在机制。在体内研究中，在C57BL/6小鼠中建立DOX诱导的HF模型，将其随机分为六组：对照组、DOX组、分别用2.5、5和10mg/kg/天剂量的Tan IIA处理的DOX组（DOX+Tan IIA）以及用200mg/kg/天剂量的N-乙酰半胱氨酸（NAC）处理的DOX组。
结果
结果表明，Tan IIA显著提高细胞活力并保护细胞免受DOX诱导的凋亡。RNA测序显示，Tan IIA改变了与凋亡信号通路相关的基因表达。在差异表达基因中，在凋亡信号传导中起关键作用的死亡结构域相关蛋白（DAXX）在Tan IIA处理下表达增加。此外，使用RNA干扰沉默DAXX的表达，这消除了Tan IIA介导的对DOX诱导凋亡的保护作用；这种作用与细胞外信号调节蛋白激酶1/2（ERK1/2）和丝裂原活化蛋白激酶（MEK）的表达有关。在体内研究中，超声心动图结果显示Tan IIA改善了心脏功能，组织形态学结果表明Tan IIA防止了心肌结构改变和肌原纤维破坏。此外，Tan IIA诱导了DAXX、p-ERK1/2和p-MEK的表达。Tan IIA还通过抑制裂解的半胱天冬酶-8、p-P38和裂解的半胱天冬酶-3的表达来抑制凋亡。
结论
我们的结果为DAXX在DOX诱导的心脏毒性中的重要作用提供了新的解释，并表明Tan IIA可能是通过激活DAXX/MEK/ERK1/2途径治疗HF的一种新的药物策略。
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