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Research Paper|Volume 11, Issue 11|pp 3536—3550

E3-ubiquitin ligase TRIM6 aggravates myocardial ischemia/reperfusion injury via promoting STAT1-dependent cardiomyocyte apoptosis

Guangwei Zeng1, Chen Lian1, Pei Yang1,2, Mingming Zheng3, He Ren1, Haiyan Wang1
  • 1Department of Cardiology, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China
  • 2Jiajiang Oil Storage Warehouse, Xining Joint Service Centre, Xining, China
  • 3Department of Health Economic Managment, The Second Affiliated Hospital of Air Force Medical University, Shaanxi, China
* Equal contribution
Received: February 5, 2019Accepted: May 22, 2019Published: June 6, 2019
https://doi.org/10.18632/aging.101995

Copyright: Zeng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Cardiomyocyte apoptosis is a major cause of myocardial ischemia/reperfusion (MI/R) injury, in which the activation of the signal transducer and activator of transcription 1 (STAT1) plays an important role. The E3-ubiquitin ligase TRIM6 has been implicated in regulating STAT1 activity, however, whether it is associated with MI/R injury and the underlying mechanism are not determined. In this study, by investigating a mouse MI/R injury model, we show that TRIM6 expression is induced in mouse heart following MI/R injury. Additionally, TRIM6 depletion reduces and its overexpression increases myocardial infarct size, serum creatine phosphokinase (CPK) level and cardiomyocyte apoptosis in mice subjected to MI/R injury, indicating that TRIM6 functions to aggravate MI/R injury. Mechanistically, TRIM6 promotes IKKε-dependent STAT1 activation, and the inhibition of IKKε or STAT1 with the specific inhibitor, CAY10576 or fludarabine, abolishes TRIM6 effects on cardiomyocyte apoptosis and MI/R injury. Similarly, TRIM6 mutant lacking the ability to ubiquitinate IKKε and induce IKKε/STAT1 activation also fails to promote cardiomyocyte apoptosis and MI/R injury. Thus, these results suggest that TRIM6 aggravates MI/R injury through promoting IKKε/STAT1 activation-dependent cardiomyocyte apoptosis, and that TRIM6 might represent a novel therapeutic target for alleviating MI/R injury.