Downregulation of cardiac PIASy inhibits Cx43 SUMOylation and ameliorates ventricular arrhythmias in a rat model of myocardial ischemia/reperfusion injury.
10.1097/CM9.0000000000002618
- Author:
Tingting WANG
1
;
Jinmin LIU
1
;
Chenchen HU
1
;
Xin WEI
1
;
Linlin HAN
1
;
Afang ZHU
1
;
Rong WANG
1
;
Zhijun CHEN
2
;
Zhengyuan XIA
3
;
Shanglong YAO
1
;
Weike MAO
1
Author Information
1. Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
2. Department of Anesthesiology, Wuhan No. 1 Hospital, Wuhan, Hubei 430022, China.
3. State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, China.
- Publication Type:Journal Article
- MeSH:
Rats;
Male;
Animals;
Myocardial Reperfusion Injury/metabolism*;
Connexin 43/genetics*;
Sumoylation;
Down-Regulation;
Rats, Sprague-Dawley;
Arrhythmias, Cardiac/drug therapy*;
Myocardial Ischemia/metabolism*;
RNA, Small Interfering/metabolism*
- From:
Chinese Medical Journal
2023;136(11):1349-1357
- CountryChina
- Language:English
-
Abstract:
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.
