Chia-Tung Wu1, Xiao-Yan Qi2, Hai Huang2, Patrice Naud2, Kristin Dawson3, Yung-Hsin Yeh4, Masahide Harada5, Chi-Tai Kuo4, Stanley Nattel6. 1. 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. 2. Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8. 3. 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. 4. Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China. 5. 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. 6. 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.
Abstract
AIMS: 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). METHODS AND 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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). METHODS AND RESULTS:Left atrial (LA) and ventricular (LV) fibroblasts were freshly isolated from control and CHFdogs (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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: L Chilton; S Ohya; D Freed; E George; V Drobic; Y Shibukawa; K A Maccannell; Y Imaizumi; R B Clark; I M C Dixon; W R Giles Journal: Am J Physiol Heart Circ Physiol Date: 2005-01-14 Impact factor: 4.733
Authors: Yoshiyuki Shibukawa; E Lisa Chilton; K Andrew Maccannell; Robert B Clark; Wayne R Giles Journal: Biophys J Date: 2005-03-11 Impact factor: 4.033