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Molecular Medicine

, Volume 17, Issue 11–12, pp 1179–1187 | Cite as

Overexpression of M3 Muscarinic Receptor Is a Novel Strategy for Preventing Sudden Cardiac Death in Transgenic Mice

  • Yan Liu
  • Lihua Sun
  • Zhenwei Pan
  • Yunlong Bai
  • Ning Wang
  • Jinlong Zhao
  • Chaoqian Xu
  • Zhi Li
  • Baoxin Li
  • Zhimin Du
  • Yanjie Lu
  • Xu Gao
  • Baofeng Yang
Research Article

Abstract

The present study was designed to investigate the cardiac benefits of M3 muscarinic receptor (M3-mAChR) overexpression and whether these effects are related to the regulation of the inward rectifying K+ channel by microRNA-1 (miR-1) in a conditional overexpression mouse model. A cardiac-specific M3-mAChR transgenic mouse model was successfully established for the first time in this study using microinjection, and the overexpression was confirmed by both reverse transcriptase-polymerase chain reaction and Western blot techniques. We demonstrated that M3-mAChR overexpression dramatically reduced the incidence of arrhythmias and decreased the mortality in a mouse model of myocardial ischemia-reperfusion (I/R). By using whole-cell patch techniques, M3-mAChR overexpression significantly shortened the action potential duration and restored the membrane repolarization by increasing the inward rectifying K+ current. By using Western blot techniques, M3-mAChR overexpression also rescued the expression of the inward rectifying K+ channel subunit Kir2.1 after myocardial I/R injury. This result was accompanied by suppression of upregulation miR-1. We conclude that M3-mAChR overexpression reduced the incidence of arrhythmias and mortality after myocardial I/R by protecting the myocardium from ischemia in mice. This effect may be mediated by increasing the inward rectifying K+ current by downregulation of arrhythmogenic miR-1 expression, which might partially be a novel strategy for antiarrhythmias, leading to sudden cardiac death.

Notes

Acknowledgments

This study was supported in part by the National Basic Research Program (973 Program) of China (2007CB512000/2007CB512006) and the National Natural Science Foundation of China (81072639, 30973531). We thank J Robbins for the gift of the α-MHC vector.

Supplementary material

10020_2011_17111179_MOESM1_ESM.pdf (147 kb)
Supplementary material, approximately 146 KB.

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Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Yan Liu
    • 1
  • Lihua Sun
    • 1
  • Zhenwei Pan
    • 1
  • Yunlong Bai
    • 1
  • Ning Wang
    • 1
  • Jinlong Zhao
    • 2
  • Chaoqian Xu
    • 1
  • Zhi Li
    • 1
  • Baoxin Li
    • 1
  • Zhimin Du
    • 2
  • Yanjie Lu
    • 1
  • Xu Gao
    • 3
  • Baofeng Yang
    • 1
  1. 1.Department of PharmacologyState-Province Key Laboratories of Biomedicine and PharmaceuticsHarbin, HeilongjiangChina
  2. 2.Institute of Clinical Pharmacology of the Second HospitalHarbin Medical UniversityHarbin, HeilongjiangChina
  3. 3.Department of Biochemistry and Molecular BiologyHarbin Medical UniversityHarbin, HeilongjiangChina

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