TRAF1 Exacerbates Myocardial Ischemia Reperfusion Injury via ASK1-JNK/p38 Signaling.

Abstract

Background After acute myocardial infarction, the recovery of ischemic myocardial blood flow may cause myocardial reperfusion injury, which reduces the efficacy of myocardial reperfusion. Ways to reduce and prevent myocardial ischemia/reperfusion (I/R) injury are of great clinical significance in the treatment of patients with acute myocardial infarction. TRAF1 (tumor necrosis factor receptor-associated factor 1) is an important adapter protein that is implicated in molecular events regulating immunity, inflammation, and cell death. Little is known about the role and impact of TRAF1 in myocardial I/R injury. Methods and Results TRAF1 expression is markedly induced in wild-type mice and cardiomyocytes after I/R or hypoxia/reoxygenation stimulation. I/R models were established in TRAF1 knockout mice and wild type mice (n=10 per group). We demonstrated that TRAF1 deficiency protects against myocardial I/R-induced loss of heat function, inflammation, and cardiomyocyte death. In addition, overexpression of TRAF1 in primary cardiomyocytes promotes hypoxia/reoxygenation-induced inflammation and apoptosis in vitro. Mechanistically, TRAF1 promotes myocardial I/R injury through regulating ASK1 (apoptosis signal-regulating kinase 1)-mediated JNK/p38 (c-Jun N-terminal kinase/p38) MAPK (mitogen-activated protein kinase) cascades. Conclusions Our results indicated that TRAF1 aggravates the development of myocardial I/R injury by enhancing the activation of ASK1-mediated JNK/p38 cascades. Targeting the TRAF1-ASK1-JNK/p38 pathway provide feasible therapies for cardiac I/R injury.

• Authors: Weipan Xu, Li Zhang, Yi Zhang, Kai Zhang, Yongbo Wu, Daoqun Jin
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 8 Issue 21 Pg. e012575 (11 05 2019) ISSN: 2047-9980 [Electronic] England
• PMID: 31650881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TNF Receptor-Associated Factor 1
• MAP Kinase Kinase Kinase 5
• Map3k5 protein, mouse

Topics

• Animals
• Disease Progression
• MAP Kinase Kinase Kinase 5 (physiology)
• MAP Kinase Signaling System (physiology)
• Mice
• Mice, Knockout
• Myocardial Reperfusion Injury (etiology)
• TNF Receptor-Associated Factor 1 (physiology)