SNX17 produces anti-arrhythmic effects by preserving functional SERCA2a protein in myocardial infarction.

Abstract

BACKGROUND:

Sorting nexin 17 (SNX17) is a critical cytoplasmic adaptor protein that regulates endosomal trafficking of membrane proteins to determine their recycling and/or degradation. The potential role of SNX17 in cardiovascular pathophysiology has not been reported.

METHODS AND RESULTS:

Cardiac arrhythmias were monitored using standard limb lead II electrocardiograph, and cardiac performances were determined by echocardiography in a rat model of myocardial infarction (MI) created by left anterior descending coronary artery ligation. We found that SNX17 was substantially downregulated in ischemic myocardium. The downregulation contributed to the cardiac electrical disturbances and contractile dysfunction as SNX17 replacement mitigated the detrimental alterations of MI hearts. Specifically, silence of SNX17 expression using RNA interference caused intracellular Ca2+ overload as revealed by the abnormal rise of resting [Ca2+]i and deceleration of Ca2+ decay, whereas SNX17 overexpression using vectors elicited the opposite effects. Moreover, the protein level of SERCA2a was significantly decreased by silencing SNX17. Immunohistochemistry indicated that SNX17 and SERCA2a were co-localized, and co-immunoprecipitation revealed the binding between the phox-homology domain of SNX17 and SERCA2a protein. Furthermore, lysosome inhibitor chloroquine prevented SNX17 silencing-induced reduction of SERCA2a protein level.

CONCLUSION:

Abnormal downregulation of SNX17 contributes to ischemic damages of cardiac electrophysiology and contractile function. SNX17 is an endogenous anti-arrhythmic factor acting by preserving functional SERCA2a protein in MI thereby offering a new strategy for the management of MI to alleviate ischemic myocardial injuries.

• Authors: Dandan Zhao, Xuelian Li, Haihai Liang, Nan Zheng, Zhenwei Pan, Yuhong Zhou, Xiao Liu, Ming Qian, Bozhi Xu, Ying Zhang, Ying Feng, Muge Qili, Qiuxia Wu, Baofeng Yang, Hongli Shan
• Journal: International journal of cardiology (Int J Cardiol) Vol. 272 Pg. 298-305 (Dec 01 2018) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 30025651 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• SNX17 protein, human
• Sorting Nexins
• Sarcoplasmic Reticulum Calcium-Transporting ATPases

Topics

• Animals
• Cells, Cultured
• Male
• Myocardial Infarction (genetics, metabolism, prevention & control)
• Rats
• Rats, Wistar
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (antagonists & inhibitors, biosynthesis, genetics)
• Sorting Nexins (biosynthesis, genetics)