Cardiac-targeted <italic style="font-style: italic">PIASy</italic> gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Na<sub>v</sub>1.5 downregulation and ventricular arrhythmias

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

doi:10.1186/s40779-022-00415-x

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Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Na_v1.5 downregulation and ventricular arrhythmias

RESEARCH | Updated：2023-07-21

- Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Na_v1.5 downregulation and ventricular arrhythmias
- Military Medical Research Vol. 10, Issue 3, Pages: 342-358(2023)
- Affiliations：
  
  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
- Author bio：
  
  * wangtt201307@163.com;
  1984xH0556@hust.edu.cn
- Funds：
- DOI：10.1186/s40779-022-00415-x
  CLC：
- Published：2023-06
- Accepted：
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Cite this article as: Hu CC, Wei X, Liu JM, Han LL, Xia CK, Wu J, et al. Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Na_v1.5 downregulation and ventricular arrhythmias. Mil Med Res. 2022;9(1):58.
DOI：

Cite this article as: Hu CC, Wei X, Liu JM, Han LL, Xia CK, Wu J, et al. Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Na_v1.5 downregulation and ventricular arrhythmias. Mil Med Res. 2022;9(1):58. DOI： 10.1186/s40779-022-00415-x.

摘要

Abstract

Background:

Abnormal myocardial voltage-gated sodium channel 1.5 (Na

1.5) 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 Na

1.5. PIASy activity is increased after myocardial I/R

but it is unclear whether this is attributable to plasma membrane Na

1.5 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 (

0.01)

with increased SUMO2/3 modification of Cav-3 and reduced membrane Na

1.5 density (

0.01). AAV9-PIASy shRNA intraventricular injection into the rat heart down-regulated PIASy after I/R

at both mRNA and protein levels (

0.05

. Scramble-shRNA+I/R group)

decreased SUMO-modified Cav-3 levels

enhanced Cav-3 binding to Na

1.5

and prevented I/R-induced decrease of Na

1.5 and Cav-3 co-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;

0.05

. Scramble-shRNA+I/R group) and a significantly reduced arrhythmia score (

0.01

. 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 (

0.05

. 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 promoted Cav-3 modification by SUMO2/3 and Na

1.5/Cav-3 dissociation after H/R. Mutation of SUMO consensus lysine sites in Cav-3 (K38R or K144R) altered the membrane expression levels of Na

1.5 and Cav-3 before and after H/R in HEK293T cells.

Conclusions:

I/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Na

1.5-related ventricular arrhythmias. Cardiac-targeted PIASy silencing mediated Cav-3 deSUMOylation and partially prevented I/R-induced Na

1.5 downregulation in the plasma membrane of cardiomyocytes

and subsequent ventricular arrhythmias in rats. PIASy was identified as a potential therapeutic target for life-threatening arrhythmias in patients with ischemic heart diseases.

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Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias

DOI：10.1186/s40779-022-00415-x

摘要

Abstract

关键词

Keywords

references

Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Na_v1.5 downregulation and ventricular arrhythmias