Li Ming-Rui, Yao Bi-Feng, Tang Can, Luo Xiu-Ju, Peng Jun
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; GCP Office, The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang 455000, China.
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
Toxicol Appl Pharmacol. 2025 Sep;502:117448. doi: 10.1016/j.taap.2025.117448. Epub 2025 Jun 20.
Pyroptosis is one of the major forms of cardiomyocyte death following ischemia/reperfusion (I/R). Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)/Tumor necrosis factor receptor associated factor 6 (TRAF6) pathway is involved in cardiomyocyte pyroptosis in mouse heart following I/R, and telaprevir, a hepatitis C virus protease inhibitor, has been predicted as a potential inhibitor of MALT1. This study aims to explore the effect of telaprevir on I/R-induced cardiomyocyte pyroptosis. The C57BL/6J mouse was subjected to 45 min-ischemia plus 24 h-reperfusion to establish the myocardial I/R injury model, while H9c2 cardiomyocytes were exposed to hypoxia for 8 h plus reoxygenation for 24 h (H/R) to simulate the I/R pathological process in vitro. Compared to the control group, pyroptosis was significantly increased in the I/R-treated mouse heart or the H/R-treated cardiomyocytes, evidenced by the elevated GSDMD and caspase-11 cleavage. Compared to the vehicle, telaprevir reduced myocardial infarcted size and cleavage of caspase-11 and gasdermin D (GSDMD) in mouse heart following I/R and cultured cardiomyocytes subjected to H/R in a dose-dependent manner. Mechanistically, telaprevir inhibited the recruitment of TRAF6 by MALT1, concomitant with the reduced recruitment of caspase-11 by TRAF6, and in turn, attenuated caspase-11 K63 poly-ubiquitination and activation, which was further confirmed by knockdown of TRAF6. Based on these results, we concluded that telaprevir could protect mouse heart against I/R injury by reducing caspase-11-dependent pyroptosis through inhibition of MALT1/TRAF6 pathway.
焦亡是心肌缺血/再灌注（I/R）后心肌细胞死亡的主要形式之一。黏膜相关淋巴组织淋巴瘤易位蛋白1（MALT1）/肿瘤坏死因子受体相关因子6（TRAF6）信号通路参与I/R后小鼠心脏心肌细胞焦亡，丙型肝炎病毒蛋白酶抑制剂特拉匹韦被预测为MALT1的潜在抑制剂。本研究旨在探讨特拉匹韦对I/R诱导的心肌细胞焦亡的影响。对C57BL/6J小鼠进行45分钟缺血加24小时再灌注以建立心肌I/R损伤模型，同时将H9c2心肌细胞暴露于缺氧8小时加复氧24小时（H/R）以在体外模拟I/R病理过程。与对照组相比，I/R处理的小鼠心脏或H/R处理的心肌细胞中焦亡显著增加，表现为GSDMD和半胱天冬酶-11裂解增加。与载体相比，特拉匹韦以剂量依赖性方式减少I/R后小鼠心脏和H/R处理的培养心肌细胞中的心肌梗死面积以及半胱天冬酶-11和gasdermin D（GSDMD）的裂解。机制上，特拉匹韦抑制MALT1对TRAF6的募集，同时减少TRAF6对半胱天冬酶-11的募集，进而减弱半胱天冬酶-11的K63多聚泛素化和激活，敲低TRAF6进一步证实了这一点。基于这些结果，我们得出结论，特拉匹韦可通过抑制MALT1/TRAF6信号通路减少半胱天冬酶-11依赖性焦亡，从而保护小鼠心脏免受I/R损伤。
