Identification of TRAF1 as a crucial regulator of inflammatory and oxidative injury in acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is governed by intricate molecular networks. The precise role of tumor necrosis factor receptor-associated factor 1 (TRAF1) in AMI pathogenesis remains incompletely understood. This study aimed to delineate the function, regulation, and therapeutic potential of TRAF1 in AMI. METHODS: Transcriptomic analysis of the GSE166780 dataset identified key genes involved in AMI. Expression of TRAF1 was validated in clinical plasma samples. In vitro and in vivo models of hypoxia/reoxygenation (H/R) or myocardial ischemia/reperfusion (MI/R) were used. Functional assays included cytokine measurement, oxidative stress detection, and viability and apoptosis assessment. Mechanisms involving upstream regulators USP1 and ATF2 were investigated via Co-IP, ubiquitination, luciferase reporter, ChIP, and stability assays. Drug screening and molecular docking were performed. RESULTS: Transcriptomic analysis identified TRAF1 as a key factor in AMI. TRAF1 was upregulated in AMI patients and H/R-exposed AC16 cardiomyocytes. TRAF1 knockdown mitigated H/R-induced inflammation, oxidative stress, and apoptosis in AC16 cardiomyocytes in vitro, and improved cardiac function post-MI/R in mice. Mechanistically, USP1 stabilized TRAF1 protein likely through deubiquitination, while ATF2 transcriptionally activated TRAF1. Moreover, the USP1/TRAF1 axis promoted NF-κB pathway activation. The compound parthenolide was found to exert protective effects against H/R injury, at least in part, through TRAF1 downregulation. CONCLUSION: This study suggests that TRAF1 is a central regulator of inflammatory and oxidative injury in AMI, modulated by ATF2 and USP1. Our in vitro experiments suggest that parthenolide attenuates H/R-induced injury, at least in part, through TRAF1 downregulation. Consequently, TRAF1 emerges as a promising therapeutic target warranting further investigation in preclinical models.