Wang Yaohui, Zhang Hailong, Wang Zhizeng, Wei Yinxiang, Wang Mingli, Liu Meichen, Wang Xuance, Jiang Yinan, Shi Gongning, Zhao Dongmei, Yang Zhengyan, Ren Zhiguang, Li Jing, Zhang Zhenkai, Wang Zhenfeng, Zhang Bei, Zong Beibei, Lou Xueke, Liu Chengguo, Wang Zihui, Zhang Hao, Tao Ningya, Li Xuefang, Zhang Xingkun, Guo Yafei, Ye Yang, Qi Yu, Li Hui, Wang Man, Guo Rongxin, Cheng Guanchang, Li Shulian, Zhang Jun, Liu Guangchao, Chai Lihui, Lou Qiang, Li Xia, Cui Xiukun, Gao Erhe, Dong Zheng, Hu Yanzhong, Chen Youhai H, Ma Yuanfang
Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cell and Molecular Immunology, School of Medical Sciences, Henan University, Kaifeng 475004, P.R. China.
Henan University affiliated Huaihe Hospital, Kaifeng 475004, P.R. China.
Sci Transl Med. 2020 Apr 22;12(540). doi: 10.1126/scitranslmed.aaw3172.
Myocardial infarction (MI) is a leading cause of death worldwide for which there is no cure. Although cardiac cell death is a well-recognized pathological mechanism of MI, therapeutic blockade of cell death to treat MI is not straightforward. Death receptor 5 (DR5) and its ligand TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] are up-regulated in MI, but their roles in pathological remodeling are unknown. Here, we report that blocking TRAIL with a soluble DR5 immunoglobulin fusion protein diminished MI by preventing cardiac cell death and inflammation in rats, pigs, and monkeys. Mechanistically, TRAIL induced the death of cardiomyocytes and recruited and activated leukocytes, directly and indirectly causing cardiac injury. Transcriptome profiling revealed increased expression of inflammatory cytokines in infarcted heart tissue, which was markedly reduced by TRAIL blockade. Together, our findings indicate that TRAIL mediates MI directly by targeting cardiomyocytes and indirectly by affecting myeloid cells, supporting TRAIL blockade as a potential therapeutic strategy for treating MI.
心肌梗死（MI）是全球主要的死亡原因之一，目前尚无治愈方法。虽然心脏细胞死亡是心肌梗死公认的病理机制，但通过治疗性阻断细胞死亡来治疗心肌梗死并非易事。死亡受体5（DR5）及其配体TRAIL[肿瘤坏死因子（TNF）相关凋亡诱导配体]在心肌梗死中上调，但其在病理重塑中的作用尚不清楚。在此，我们报告，用可溶性DR5免疫球蛋白融合蛋白阻断TRAIL可通过防止大鼠、猪和猴的心脏细胞死亡和炎症来减轻心肌梗死。从机制上讲，TRAIL诱导心肌细胞死亡，并募集和激活白细胞，直接和间接导致心脏损伤。转录组分析显示梗死心脏组织中炎性细胞因子表达增加，而TRAIL阻断可显著降低这种表达。总之，我们的研究结果表明，TRAIL通过靶向心肌细胞直接介导心肌梗死，并通过影响髓样细胞间接介导心肌梗死，支持将TRAIL阻断作为治疗心肌梗死的潜在治疗策略。
