Research ArticleMyocardial Infarction

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

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Science Translational Medicine  22 Apr 2020:
Vol. 12, Issue 540, eaaw3172
DOI: 10.1126/scitranslmed.aaw3172

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Curbing cardiac cell death

Cell death resulting from myocardial infarction contributes to cardiac dysfunction and pathological remodeling. Wang et al. found that blocking tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a ligand of death receptor 5 (DR5), reduced inflammation and improved cardiac function after myocardial infarction in multiple animal models. Treating rodents, pigs, and monkeys with a soluble DR5 fusion protein within 2 hours after inducing ischemia reduced recruitment of myeloid cells to injured heart tissue and blunted cell death. TRAIL blockade could offer potential cardiac protection in the setting of myocardial infarction.


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.

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