SENP2-mediated SERCA2a deSUMOylation increases calcium overload in cardiomyocytes to aggravate myocardial ischemia/reperfusion injury  

作　　者：Yuanyuan Luo Shuaishuai Zhou Tao Xu Wanling Wu Pingping Shang Shuai Wang Defeng Pan Dongye Li 

机构地区：[1]Department of Cardiology,The Affiliated Hospital of Xuzhou Medical University,Xuzhou,Jiangsu 221006,China [2]Institute of Cardiovascular Disease Research,Xuzhou Medical University,Xuzhou,Jiangsu 221002,China

出　　处：《Chinese Medical Journal》2023年第20期2496-2507,共12页中华医学杂志（英文版）

基　　金：supported by grants from the Natural Science Foundation of Jiangsu Province(No.BK20190988);the Scientific Research Project of Jiangsu Health Committee(No.H2018005);the Key Research and Development Program of Xuzhou(No.KC20097);the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX21_2671).

摘　　要：Background:Sarcoplasmic reticulum calcium ATPase 2a(SERCA2a)is a key protein that maintains myocardial Ca2+homeostasis.The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation(small ubiquitinlike modifier)process after ischemia/reperfusion injury(I/RI)in vitro and in vivo.Methods:Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout(KO)and wildtype mice with I/RI were compared.SUMO-relevant protein expression and localization were detected by quantitative real-time PCR(RT-qPCR),Western blotting,and immunofluorescence in vitro and in vivo.Serca2a-SUMOylation,infarct size,and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes,were detected by immunoprecipitation,triphenyltetrazolium chloride(TTC)-Evans blue staining,and echocardiography respectively.Results:The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO+I/RI groups.Senp1 and Senp2 messenger ribose nucleic acid(mRNA)and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI.However,the highest levels in HL-1 cells were recorded at 12 h.Senp2 expression increased in the cytoplasm,unlike that of Senp1.Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline,reduced the infarction area,and improved cardiac function,while inhibition of Senp1 protein could not restore the above indicators.Conclusion:I/RI activated Senp1 and Senp2 protein expression,which promoted Serca2a-deSUMOylation,while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.

关 键 词：Myocardial ischemia Reperfusion injury Sarcoplasmic reticulum calcium-transporting ATPases Sentrin/SUMOspecific protease Calcium overload 

分 类 号：R542.2[医药卫生—心血管疾病]