biostudies-literatureWang YFoundation of Henan Educational CommitteeNIDDK NIH HHSNational Natural Science Foundation of China-Henan Joint FundNational Natural Science Foundation of Chinaeaaw3172https://www.ebi.ac.uk/biostudies/studies/S-EPMC9719290biostudies-literatureUnknown12(540)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 exScience translational medicineBlocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.PMC971929081670271U1404801T32 DK00778014A416008Lou QHu YLiu MGuo YZhang JRen ZZhang HDong ZLou XMa YYe YGuo RGao EWei YWang MJiang YZong BQi YWang XZhao DWang YCheng GWang ZZhang BLi HChai LLi JCui XLi XYang ZLi SZhang ZZhang XShi GChen YHLiu CTao NLiu GfalseBlocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs, and rats.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 ex2020-01-01T00:00:00Z2020 Apr2025-04-04T07:47:56.43Z2025-04-04T07:47:56.43ZS-EPMC97192903232186610.1126/scitranslmed.aaw3172