Science translational medicine · 2020
Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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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
Аннотация
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.