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Updated: Dec 23, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Blocking the death checkpoint protein TRAIL improves cardiac function after myocardial infarction in monkeys, pigs,
Yaohui Wang1, Hailong Zhang1, Zhizeng Wang1
1Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cell and Molecular Immunology, School of Medical Sciences, Henan University, Kaifeng 475004, P.R. China.
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.
Insights
Blocking tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) effectively reduced myocardial infarction (MI) in animal models by preventing heart cell death and inflammation. This suggests TRAIL blockade is a promising therapeutic strategy for treating heart attacks.
Area of Science:
- Cardiovascular Science
- Immunology
- Molecular Biology
Background:
- Myocardial infarction (MI) is a major global cause of death with no cure.
- Cardiac cell death is a key pathological feature of MI, but therapeutic strategies targeting it are complex.
- The roles of Death Receptor 5 (DR5) and its ligand TRAIL in MI-induced pathological remodeling are not well understood.
Purpose of the Study:
- To investigate the role of the TRAIL/DR5 pathway in myocardial infarction.
- To evaluate the therapeutic potential of blocking TRAIL in mitigating MI-induced cardiac damage and inflammation.
Main Methods:
- Utilized a soluble DR5 immunoglobulin fusion protein to block TRAIL in rat, pig, and monkey models of MI.
- Assessed the impact of TRAIL blockade on cardiac cell death, inflammation, and pathological remodeling.
- Employed transcriptome profiling to analyze gene expression changes in infarcted heart tissue.
Main Results:
- Blocking TRAIL significantly diminished MI, preventing cardiac cell death and reducing inflammation.
- TRAIL was found to directly induce cardiomyocyte death and indirectly promote cardiac injury by recruiting and activating leukocytes.
- TRAIL blockade markedly reduced the expression of inflammatory cytokines in infarcted heart tissue.
Conclusions:
- TRAIL plays a dual role in MI, directly targeting cardiomyocytes and indirectly affecting myeloid cells, thereby exacerbating cardiac injury.
- Blocking TRAIL presents a viable therapeutic strategy for managing myocardial infarction and its associated pathological remodeling.
