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.