Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats

Yaohui Wang, Hailong Zhang, Zhizeng Wang, Yinxiang Wei, Mingli Wang, Meichen Liu, Xuance Wang, Yinan Jiang, Gongning Shi, Dongmei Zhao, Zhengyan Yang, Zhiguang Ren, Jing Li, Zhenkai Zhang, Zhenfeng Wang, Bei Zhang, Beibei Zong, Xueke Lou, Chengguo Liu, Zihui WangHao Zhang, Ningya Tao, Xuefang Li, Xingkun Zhang, Yafei Guo, Yang Ye, Yu Qi, Hui Li, Man Wang, Rongxin Guo, Guanchang Cheng, Shulian Li, Jun Zhang, Guangchao Liu, Lihui Chai, Qiang Lou, Xia Li, Xiukun Cui, Erhe Gao, Zheng Dong, Yanzhong Hu, Youhai H. Chen, Yuanfang Ma

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbereaaw3172
JournalScience Translational Medicine
Volume12
Issue number540
DOIs
StatePublished - Apr 22 2020

ASJC Scopus subject areas

  • Medicine(all)

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    Wang, Y., Zhang, H., Wang, Z., Wei, Y., Wang, M., Liu, M., Wang, X., Jiang, Y., Shi, G., Zhao, D., Yang, Z., Ren, Z., Li, J., Zhang, Z., Wang, Z., Zhang, B., Zong, B., Lou, X., Liu, C., ... Ma, Y. (2020). Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats. Science Translational Medicine, 12(540), [eaaw3172]. https://doi.org/10.1126/scitranslmed.aaw3172