Persistent increases in Ca2+ influx through Cav1.2 shortens action potential and causes Ca2+ overload-induced afterdepolarizations and arrhythmias
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- 作者：Xiaoying Zhang ; Xiaojie Ai ; Hiroyuki Nakayama ; Biyi Chen…
- 关键词：L ; type calcium channel or Cav1.2 ; 尾2a subunit ; Afterdepolarizations ; Short QT ; Potassium currents
- 刊名：Basic Research in Cardiology
- 出版年：2016
- 出版时间：January 2016
- 年：2016
- 卷：111
- 期：1
- 全文大小：3,729 KB
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Xiaojie Ai (2) (6)
Hiroyuki Nakayama (3)
Biyi Chen (4)
David M. Harris (5)
Mingxin Tang (2)
Yuping Xie (4)
Christopher Szeto (2)
Yingxin Li (2)
Ying Li (2) (7)
Hongyu Zhang (2)
Andrea D. Eckhart (8)
Walter J. Koch (9)
Jeffery D. Molkentin (3)
Xiongwen Chen (1) (2)
1. Daping Hospital, The Third Military Medical University, Chongqing, China
2. Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA
6. School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China
3. Cincinnati Children鈥檚 Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA
4. Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA
5. College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
7. The Second Artillery General Hospital, Beijing, 100088, China
8. MedThink SciCom, Raleigh, NC, 27609, USA
9. Center for Translational Medicine and Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA - 刊物类别：Medicine
- 刊物主题：Medicine & Public Health
Cardiology - 出版者：Springer Berlin / Heidelberg
- ISSN：1435-1803
文摘
Persistent elevation of Ca2+ influx due to prolongation of the action potential (AP), chronic activation of the 尾-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca2+ influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the 尾2a subunit of Cav (Cav尾2a). DTG myocytes had increased L-type Ca2+ current (ICa-L), myocyte shortening, and Ca2+ transients. DTG mice had enhanced cardiac performance, but died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals in DTG mice. The action potential duration (APD) was shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca2+ influx and increased the peak and tail ICa-L. Enhanced ICa promoted sarcoplasmic reticulum (SR) Ca2+ overload, diastolic Ca2+ sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca2+ overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias, and conduction abnormalities. Keywords L-type calcium channel or Cav1.2 尾2a subunit Afterdepolarizations Short QT Potassium currents