2. Academic Validation
  3. Attenuation of cardiac ischemia/reperfusion injury via the decoy receptor DcR2 by targeting the PLAD domain of the death receptor DR5

Attenuation of cardiac ischemia/reperfusion injury via the decoy receptor DcR2 by targeting the PLAD domain of the death receptor DR5

  • Int J Biol Macromol. 2025 May;308(Pt 3):142529. doi: 10.1016/j.ijbiomac.2025.142529.
Lijie Zhang 1,  Xinyuan Zhang 1,  Ziting Li 2,  Tingting Mo 2,  Wanting Feng 2,  JingLun Zhang 3,  Dan Zhao 2,  Ying Wang 3,  Yinxiang Wei 4,  Yaohui Wang 5
Affiliations

Affiliations

  • 1 Joint National Laboratory for Antibody Drug Engineering, the First Affiliated Hospital, Henan University, Kaifeng, China; Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China.
  • 2 Joint National Laboratory for Antibody Drug Engineering, the First Affiliated Hospital, Henan University, Kaifeng, China.
  • 3 School of Medicine, Henan University, Kaifeng, China.
  • 4 Joint National Laboratory for Antibody Drug Engineering, the First Affiliated Hospital, Henan University, Kaifeng, China. Electronic address: yxwei@henu.edu.cn.
  • 5 Joint National Laboratory for Antibody Drug Engineering, the First Affiliated Hospital, Henan University, Kaifeng, China. Electronic address: wangyaohui2017@henu.edu.cn.
PMID: 40154678 DOI: 10.1016/j.ijbiomac.2025.142529
Abstract

Myocardial cell death caused by ischemia and hypoxia is the main cause of myocardial injury. DcR2 is the decoy receptor of TRAIL, and the role of DcR2 in myocardial ischemia/reperfusion (I/R) injury is largely unknown. Recent studies have shown that DcR2 not only binds to TRAIL as a receptor but also acts as a ligand for DR5 to block TRAIL-induced Apoptosis in vitro, but the preference of DcR2 for binding to TRAIL or DR5 in vivo remains unknown. Our study revealed that the hDcR2-Fc fusion protein plays a cardioprotective role in a mouse model of myocardial I/R injury by reducing Apoptosis. An affinity assay revealed that DcR2 has a greater affinity for DR5 than for TRAIL and that DcR2 is more inclined to bind to DR5. Mechanistic studies elucidated that deletion of PLAD eliminated the protective effect of hDcR2-Fc on heart injury caused by I/R. DcR2 forms a heterocomplex with DR5 through a similar PLAD domain. Taken together, this study revealed that DcR2 can ameliorate myocardial I/R injury by targeting DR5 to form a heterocomplex through the PLAD domain, blocking Apoptosis, thus providing a new preventive strategy for the treatment of myocardial I/R injury.

Keywords

DR5; DcR2; Ischemia/reperfusion injury; Myocardial infarction; PLAD.

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