Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Na_(v)1.5 downregulation and ventricular arrhythmias  

作　　者：Chen-Chen Hu Xin Wei Jin-Min Liu Lin-Lin Han Cheng-Kun Xia Jing Wu Tao You A-Fang Zhu Shang-Long Yao Shi-Ying Yuan Hao-Dong Xu Zheng-Yuan Xia Ting-Ting Wang Wei-Ke Mao 

机构地区：[1]Department of Anesthesiology,Institute of Anesthesiology and Critical Care Medicine,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [2]Department of Cardiology,the Second Affiliated Hospital of Soochow University,Suzhou 215004,Jiangsu,China [3]Department of Anesthesiology,Peking Union Medical College Hospital,CAMS and PUMC,Beijing 100730,China [4]Department of Pathology,University of Washington,Seattle,WA 98195,USA [5]State Key Laboratory of Pharmaceutical Biotechnology,the University of Hong Kong,Hong Kong 999077,China [6]Department of Anesthesiology,Affiliated Hospital of Guangdong Medical University,Zhanjiang 524000,Guangdong,China

出　　处：《Military Medical Research》2023年第3期342-358,共17页军事医学研究（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(81770824,81270239)。

摘　　要：Background:Abnormal myocardial voltage-gated sodium channel 1.5(Nav1.5)expression and function cause lethal ventricular arrhythmias during myocardial ischemia–reperfusion(I/R).Protein inhibitor of activated STAT Y(PIASy)-mediated caveolin-3(Cav-3)small ubiquitin-related modifier(SUMO)modification affects Cav-3 binding to the Nav1.5.PIASy activity is increased after myocardial I/R,but it is unclear whether this is attributable to plasma membrane Nav1.5 downregulation and ventricular arrhythmias.Methods:Using recombinant adeno-associated virus subtype 9(AAV9),rat cardiac PIASy was silenced using intraventricular injection of PIASy short hairpin RNA(shRNA).After two weeks,rat hearts were subjected to I/R and electrocardiography was performed to assess malignant arrhythmias.Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurements.Results:PIASy was upregulated by I/R(P<0.01),with increased SUMO2/3 modification of Cav-3 and reduced membrane Nav1.5 density(P<0.01).AAV9-PIASy shRNA intraventricular injection into the rat heart down-regulated PIASy after I/R,at both mRNA and protein levels(P<0.05 vs.Scramble-shRNA+I/R group),decreased SUMO-modified Cav-3 levels,enhanced Cav-3 binding to Nav1.5,and prevented I/R-induced decrease of Nav1.5 and Cav-3co-localization in the intercalated disc and lateral membrane.PIASy silencing in rat hearts reduced I/R-induced fatal arrhythmias,which was reflected by a modest decrease in the duration of ventricular fibrillation(VF;P<0.05 vs.Scramble-shRNA+I/R group)and a significantly reduced arrhythmia score(P<0.01 vs.Scramble-shRNA+I/R group).The anti-arrhythmic effects of PIASy silencing were also evidenced by decreased episodes of ventricular tachycardia(VT),sustained VT and VF,especially at the time 5–10 min after ischemia(P<0.05 vs.Scramble-shRNA+IR group).Using in vitro human embryonic kidney 293 T(HEK293T)cells and isolated adult rat cardiomyocyte models exposed to hypoxia/reoxygenation(H/R),we confirmed that increased PIASy promot

关 键 词：Ventricular arrhythmia Na_(v)1.5 Caveolin-3 Protein inhibitor of activated STAT Y SUMOYLATION 

分 类 号：R541.7[医药卫生—心血管疾病]