title: Disease and region-related cardiac fibroblast potassium current variations and potential functional significance.
abstract: OBJECTIVE
  Fibroblasts, which play an important role in cardiac function/dysfunction, including arrhythmogenesis, have voltage-dependent (Kv) currents of unknown importance. Here, we assessed the differential expression of Kv currents between atrial and ventricular fibroblasts from control dogs and dogs with an atrial arrhythmogenic substrate caused by congestive heart failure (CHF).
  
  
  RESULTS
  Left atrial (LA) and ventricular (LV) fibroblasts were freshly isolated from control and CHF dogs (2-week ventricular tachypacing, 240 bpm). Kv currents were measured with whole-cell voltage-clamp, mRNA by quantitative polymerase chain reaction (qPCR) and fibroblast proliferation by (3)H-thymidine incorporation. Robust voltage-dependent tetraethylammonium (TEA)-sensitive K(+) currents (IC50 ∼1 mM) were recorded. The morphologies and TEA responses of LA and LV fibroblast Kv currents were similar. LV fibroblast Kv-current densities were significantly greater than LA, and Kv-current densities were significantly less in CHF than control. The mRNA expression of Kv-channel subunits Kv1.5 and Kv4.3 was less in LA vs. LV fibroblasts and was down-regulated in CHF, consistent with K(+)-current recordings. Ca(2+)-dependent K(+)-channel subunit (KCa1.1) mRNA and currents were less expressed in LV vs. LA fibroblasts. Inhibiting LA fibroblast K(+) current with 1 mmol/L of TEA or KCa1.1 current with paxilline increased proliferation.
  
  
  CONCLUSIONS
  Fibroblast Kv-current expression is smaller in CHF vs. control, as well as LA vs. LV. KCa1.1 current is greater in LA vs. LV. Suppressing Kv current with TEA enhances fibroblast proliferation, suggesting that Kv current might act to check fibroblast proliferation and that reduced Kv current in CHF may contribute to fibrosis. Fibroblast Kv-current remodelling may play a role in the atrial fibrillation (AF) substrate; modulating fibroblast K(+) channels may present a novel strategy to prevent fibrosis and AF.
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8 Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8.
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8 Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Kristin
authors.initials: K
authors.lastname: Dawson
authors.affiliation: Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8 Department of Cardiology, Hamamatsu Medical Center, Hamamatsu, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Harada
authors.affiliation: Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Kuo
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8 Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada stanley.nattel@icm-mhi.org.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology; D004285:Dogs; D005347:Fibroblasts / Q000502:physiology*; D005355:Fibrosis; D006333:Heart Failure / Q000150:complications / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
chemical_list: D024642:Potassium Channels, Voltage-Gated; D013757:Tetraethylammonium Compounds
keywords: Congestive heart failure; Fibroblast; Ionic channel; Proliferation; Remodelling