Background:Dysfunction of the gap junction channel protein connexin 43(Cx43)contributes to myocardial ischemia/reperfusion(I/R)-induced ventricular arrhythmias.Cx43 can be regulated by small ubiquitin-like modifier(SU...Background:Dysfunction of the gap junction channel protein connexin 43(Cx43)contributes to myocardial ischemia/reperfusion(I/R)-induced ventricular arrhythmias.Cx43 can be regulated by small ubiquitin-like modifier(SUMO)modification.Protein inhibitor of activated STAT Y(PIASy)is an E3 SUMO ligase for its target proteins.However,whether Cx43 is a target protein of PIASy and whether Cx43 SUMOylation plays a role in I/R-induced arrhythmias are largely unknown.Methods:Male Sprague-Dawley rats were infected with PIASy short hairpin ribonucleic acid(shRNA)using recombinant adeno-associated virus subtype 9(rAAV9).Two weeks later,the rats were subjected to 45 min of left coronary artery occlusion followed by 2 h reperfusion.Electrocardiogram was recorded to assess arrhythmias.Rat ventricular tissues were collected for molecular biological measurements.Results:Following 45 min of ischemia,QRS duration and QTc intervals statistically significantly increased,but these values decreased after transfecting PIASy shRNA.PIASy downregulation ameliorated ventricular arrhythmias induced by myocardial I/R,as evidenced by the decreased incidence of ventricular tachycardia and ventricular fibrillation,and reduced arrythmia score.In addition,myocardial I/R statistically significantly induced PIASy expression and Cx43 SUMOylation,accompanied by reduced Cx43 phosphorylation and plakophilin 2(PKP2)expression.Moreover,PIASy downregulation remarkably reduced Cx43 SUMOylation,accompanied by increased Cx43 phosphorylation and PKP2 expression after I/R.Conclusion:PIASy downregulation inhibited Cx43 SUMOylation and increased PKP2 expression,thereby improving ventricular arrhythmias in ischemic/reperfused rats heart.展开更多
Systemic inflammatory response following myocardial ischemia-reperfusion injury(IRI)to a specific organ may cause injuries.Ischemic post-conditioning(IPostC)has emerged as a promising method for myocardial protection ...Systemic inflammatory response following myocardial ischemia-reperfusion injury(IRI)to a specific organ may cause injuries.Ischemic post-conditioning(IPostC)has emerged as a promising method for myocardial protection against IRI both in experimental and in clinical settings.Enhancement of endogenous nitric oxide(NO)is one of the major mechanisms by which IPostC confers cardioprotection.However,the sensitivity of the diabetic heart to IPostC is impaired and the underlying mechanism is unknown.Adiponectin(APN)is an adipocyte-derived plasma protein with anti-diabetic and anti-inflammatory properties.Plasma levels of APN are decreased in obese subjects and in patients with type 2 diabetes.APN supplementation has been shown to increase NO production and attenuate myocardial IRI in normal(non-diabetic)animals.However,the effect of APN on myocardial injury in diabetic subjects,especially its potential in restoring the sensitivity of the diabetic heart to IPostC has not been investigated.In the current paper,we discussed the possible reasons why the myocardium of diabetic subjects loses sensitivity to IPostC and also highlighted the potential effectiveness and mechanism of APN in restoring IPostC cardioprotection in diabetes.This review proposes to conduct studies that may facilitate the development of novel and optimal therapies to enhance cardioprotection in patients with severe diseases such as diabetes.展开更多
基金National Natural Science Foundation of China(Nos.81770824 and 81470251)
文摘Background:Dysfunction of the gap junction channel protein connexin 43(Cx43)contributes to myocardial ischemia/reperfusion(I/R)-induced ventricular arrhythmias.Cx43 can be regulated by small ubiquitin-like modifier(SUMO)modification.Protein inhibitor of activated STAT Y(PIASy)is an E3 SUMO ligase for its target proteins.However,whether Cx43 is a target protein of PIASy and whether Cx43 SUMOylation plays a role in I/R-induced arrhythmias are largely unknown.Methods:Male Sprague-Dawley rats were infected with PIASy short hairpin ribonucleic acid(shRNA)using recombinant adeno-associated virus subtype 9(rAAV9).Two weeks later,the rats were subjected to 45 min of left coronary artery occlusion followed by 2 h reperfusion.Electrocardiogram was recorded to assess arrhythmias.Rat ventricular tissues were collected for molecular biological measurements.Results:Following 45 min of ischemia,QRS duration and QTc intervals statistically significantly increased,but these values decreased after transfecting PIASy shRNA.PIASy downregulation ameliorated ventricular arrhythmias induced by myocardial I/R,as evidenced by the decreased incidence of ventricular tachycardia and ventricular fibrillation,and reduced arrythmia score.In addition,myocardial I/R statistically significantly induced PIASy expression and Cx43 SUMOylation,accompanied by reduced Cx43 phosphorylation and plakophilin 2(PKP2)expression.Moreover,PIASy downregulation remarkably reduced Cx43 SUMOylation,accompanied by increased Cx43 phosphorylation and PKP2 expression after I/R.Conclusion:PIASy downregulation inhibited Cx43 SUMOylation and increased PKP2 expression,thereby improving ventricular arrhythmias in ischemic/reperfused rats heart.
文摘Systemic inflammatory response following myocardial ischemia-reperfusion injury(IRI)to a specific organ may cause injuries.Ischemic post-conditioning(IPostC)has emerged as a promising method for myocardial protection against IRI both in experimental and in clinical settings.Enhancement of endogenous nitric oxide(NO)is one of the major mechanisms by which IPostC confers cardioprotection.However,the sensitivity of the diabetic heart to IPostC is impaired and the underlying mechanism is unknown.Adiponectin(APN)is an adipocyte-derived plasma protein with anti-diabetic and anti-inflammatory properties.Plasma levels of APN are decreased in obese subjects and in patients with type 2 diabetes.APN supplementation has been shown to increase NO production and attenuate myocardial IRI in normal(non-diabetic)animals.However,the effect of APN on myocardial injury in diabetic subjects,especially its potential in restoring the sensitivity of the diabetic heart to IPostC has not been investigated.In the current paper,we discussed the possible reasons why the myocardium of diabetic subjects loses sensitivity to IPostC and also highlighted the potential effectiveness and mechanism of APN in restoring IPostC cardioprotection in diabetes.This review proposes to conduct studies that may facilitate the development of novel and optimal therapies to enhance cardioprotection in patients with severe diseases such as diabetes.