Studies On The Mechanisms Of SENP3 Induced Myocardial Ischemia/Reperfusion Injury

Objective: We aim to investigate the effects of SENP3 on myocardial ischemia/reperfusion(MI/R)injury and to determine its underlying mechanisms via si RNA-mediated cardiac specific gene silencing and adenovirus-mediated cardiac SENP3 overexpression.Methods: The eight-week old male C57BL/6 mice were randomly assigned to the following groups: sham,vehicle,control si RNA,SENP3 si RNA,control adenovirus,SENP3 adenovirus,saline and Mdivi-1.The groups of sham,vehicle,control si RNA,SENP3 si RNA,control adenovirus and SENP3 adenovirus were subjected to ischemia for 30 minutes while the groups of DMSO and Mdivi-1 were intraperitoneal injectioned with DMSO and Mdivi-1 after 15 minutes of myocardial infaction.Subsequently,these mice were given reperfusion for 3 hours(for myocardial apoptosis,oxidative stress and inflammatory reaction)or 24 hours(for infarct size and cardiac function).The area of myocardial infarct size was assessed via Evans blue-TTC double staining.Cardiac function was evaluated by echocardiographic measurements.Moreover,the mechanism underlying effects of SENP3 on MI/R injury was determined by TUNEL,transmission electron microscopy,caspases activity assay,Western Blot,and quantitative PCR.Results: SENP3 expression was increased in heart tissue with MI/R.SENP3 deficiency amelioarated myocardial infarct size,improved both viable myocardium metabolism and cardiac function while SENP3 overexpression exacerbated myocardial infarct size,deteriorated both viable myocardium metabolism and cardiac function.Mechanistic studies indicated that SENP3 silencing ameliorated myocardial apoptosis mainly via suppression of endoplasmic-reticulum stress and mitochondrial mediated apoptosis pathways.Further molecular analysis revealed that SENP3 promoted mitochondrial translocation of dynamin-related protein 1(Drp1)in reperfused mypcardium.In addition,mitochondrial division inhibitor-1,a pharmacological inhibitor of Drp1,significantly attenuated theexaggerated mitochondrial abnormality and cardiac injury by SENP3 overexpression after MIR injury.Conclusion: Taken together,these data suggested that SENP3 upregulation pivotally contributes to MIR injury in a Drp1 dependent manner,and SENP3 suppression may hold therapeutic promise for constraining MIR injury,which providing theoretical foundation for future clinical applications.