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.
Highlights
Myocardial infarction (MI) is one of the leading causes of death and disability worldwide [1]
We found that TRIM6 was elevated and functioned to aggravate Myocardial ischemia/reperfusion (MI/R) injury, which was demonstrated to be mediated by signal transducer and activator of transcription 1 (STAT1)-promoted cardiomyocyte apoptosis, establishing a causal link between an E3-ubiquitin ligase with MI/R injury pathology
QRT-PCR analysis showed that compared with sham group, the transcript level of Trim6 was increased in the heart after MI/R injury, which peaked at 24 hr and declined thereafter (Figure 1A)
Summary
Myocardial infarction (MI) is one of the leading causes of death and disability worldwide [1]. MI originates from the shortage of myocardial blood supply, which is commonly caused by the intracoronary thrombus-induced occlusion of a coronary artery [2]. The mainstay therapeutic option for reducing myocardial ischemic injury is timely reperfusion. Reperfusion preserves myocardial viability and function through a reversal of ischemia, itself induces cardiomyocyte death and increases MI size, known as myocardial reperfusion injury, which undermines the therapeutic benefit [3]. Myocardial ischemia/reperfusion (MI/R) injury is a complicated pathological condition and represents a major clinical problem, for which there is still no effective therapy. It is increasingly recognized that the irreversible cardiomyocyte apoptosis plays a critical role in MI/R injury, and the anti-apoptotic strategy offers a therapeutic opportunity for reducing MI/R injury [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
