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

Abstract

BackgroundAfter 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.ConclusionsOur 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.

Exosomes from human umbilical cord mesenchymal stem cells attenuate the inflammation of severe steroid-resistant asthma by reshaping macrophage polarization

“…Tumor necrosis factor receptor-associated factor 1 (TRAF1) was found to be significantly downregulated in LPS-stimulated macrophages with MSC-Exo treatment. TRAF1 is an important cytoplasmic adaptor protein involved in regulating immunity, inflammation, and apoptosis [ 41 ]. A study by Wan et al showed that TRAF1 ablation reduced inflammation and attenuated lung damage in LPS-induced acute lung injury [ 42 ].…”

Melatonin Ameliorates MI-Induced Cardiac Remodeling and Apoptosis through a JNK/p53-Dependent Mechanism in Diabetes Mellitus

“…JNK is also considered an essential modulator for mitochondrial homeostasis and apoptosis in the onset and progression of heart failure [47,51,52]. Activation of JNK/p38 cascades has been demonstrated to aggravate the development of MI/R injury [53]. However, the roles of JNK in diabetic MI…”

Roles of TRAFs in Ischemia-Reperfusion Injury

“…Subsequently, it has also been verified that the TRAF1/ASK1 axis promotes liver IRI and myocardial IRI ( Zhang et al, 2014 ; Huang X. et al, 2019 ; Xu W. et al, 2019 ). Liver IRI is a common pathological process that occurs in hemorrhagic shock, trauma, liver resection, and liver transplantation, which lead to early allograft dysfunction (EAD), an important cause of morbidity and mortality in liver transplant recipients ( Monga, 2018 ; Ni et al, 2019 ; Nakamura et al, 2020 ).…”

“…According to current research, TRAF1 plays a vital role in cerebral, liver, and myocardial IRI ( Lu et al, 2013 ; Zhang et al, 2014 ; Huang X. et al, 2019 ; Xu W. et al, 2019 ). Cerebral IRI is the main culprit causing ischemic stroke, accounting for ∼80% of total stroke cases, which has caused adult neurological disability globally and presented a very high mortality rate yearly ( Li et al, 2019d , e ).…”

“…In myocardial IRI, TRAF1-KO mice showed decreased cardiomyocyte apoptosis and milder inflammatory response than the TRAF1 wild-type (WT) mice. Explicitly, TRAF1 aggravated primary neonatal cardiomyocyte inflammation and apoptosis via promoting the ASK1/JNK/p38 cascades in response to H/R ( Xu W. et al, 2019 ). However, TRAF1 is also expressed in fibroblasts and endothelial cells of the heart.…”