title: Heart-specific overexpression of the human short CLC-3 chloride channel isoform limits myocardial ischemia-induced ERP and QT prolongation.
abstract: BACKGROUND
  Ischemia causes myocardial infarction and arrhythmias. Up-regulation of cardiac CLC-3 chloride channels is important for ischemic preconditioning-induced second-window protection against myocardial infarction. But its consequences in ischemia-induced electrical remodeling are still unknown.
  
  
  METHODS
  The recently-characterized heart-specific overexpression of human short CLC-3 isoform (hsCLC-3(OE)) mice was used to study the effects of CLC-3 up-regulation on cardiac electrophysiology under ischemia/reperfusion conditions. In vivo surface electrocardiography (ECG) and intracardiac electrophysiology (ICEP) were used to compare the electrophysiological properties of age-matched wild-type (Clcn3(+/+)) and hsCLC-3(OE) mice under control and myocardial ischemia-reperfusion conditions.
  
  
  RESULTS
  QT and QTc intervals of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice under control, ischemia and reperfusion conditions. In the ICEP, ventricular effective refractory period (VERP) of hsCLC-3(OE) mice (26.7±1.7ms, n=6) was significantly shorter than that of Clcn3(+/+) mice (36.9±2.8ms, n=8, P<0.05). Under ischemia condition, both VERP (19.8±1.3ms) and atrial effective refractory period (AERP, 34.8±2.5ms) of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice (35.2±3.0ms and 45.8±1.6ms, P<0.01, respectively). Wenckebach atrioventricular nodal block point (AVBP, 91.13±4.08ms) and 2:1 AVBP (71.3±3.8ms) of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice (102.0±2.0ms and 84.1±2.8ms, P<0.05, respectively). However, no differences of ICEP parameters between hsCLC-3(OE) and Clcn3(+/+) mice were observed under reperfusion conditions.
  
  
  CONCLUSIONS
  Heart-specific overexpression of hsCLC-3 limited the ischemia-induced QT and ERP prolongation and postponed the advancements of Wenckebach and 2:1 AVBP. CLC-3 up-regulation may serve as an important adaptive mechanism against myocardial ischemia.
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China; Laboratory of Cardiovascular Phenomics, University of Nevada School of Medicine, Reno, NV 89557-0318, USA; Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557-0318, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Laboratory of Cardiovascular Phenomics, University of Nevada School of Medicine, Reno, NV 89557-0318, USA; Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557-0318, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. Electronic address: drliyigang@outlook.com.
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557-0318, USA.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Burkin
authors.affiliation: Laboratory of Cardiovascular Phenomics, University of Nevada School of Medicine, Reno, NV 89557-0318, USA; Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557-0318, USA. Electronic address: dduan@medicine.nevada.edu.
authors.forename: Dayue Darrel
authors.initials: DD
authors.lastname: Duan
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000378:metabolism*; D004195:Disease Models, Animal; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D020033:Protein Isoforms
keywords: Arrhythmia; Chloride channels; ECG; Electrophysiology; Ion channels; Ischemia; Torsade de pointes