Wu Chia-Tung, Qi Xiao-Yan, Huang Hai, Naud Patrice, Dawson Kristin, Yeh Yung-Hsin, Harada Masahide, Kuo Chi-Tai, Nattel Stanley
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.
Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger St. E., Montreal, QC, Canada H1T 1C8.
Cardiovasc Res. 2014 Jun 1;102(3):487-96. doi: 10.1093/cvr/cvu055. Epub 2014 Mar 4.
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).
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.
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.
成纤维细胞在心脏功能/功能障碍（包括心律失常的发生）中起重要作用，其具有电压依赖性（Kv）电流，但其重要性尚不清楚。在此，我们评估了对照犬和患有由充血性心力衰竭（CHF）引起的房性心律失常基质的犬的心房和心室成纤维细胞之间Kv电流的差异表达。
从对照犬和CHF犬（2周心室快速起搏，240次/分钟）新鲜分离左心房（LA）和心室（LV）成纤维细胞。用全细胞膜片钳测量Kv电流，用定量聚合酶链反应（qPCR）测量mRNA，用（3）H-胸腺嘧啶核苷掺入法测量成纤维细胞增殖。记录到强大的电压依赖性四乙铵（TEA）敏感钾（K+）电流（IC50约1 mM）。LA和LV成纤维细胞Kv电流的形态和TEA反应相似。LV成纤维细胞Kv电流密度显著大于LA，且CHF中的Kv电流密度显著低于对照。Kv通道亚基Kv1.5和Kv4.3的mRNA表达在LA成纤维细胞与LV成纤维细胞中较低，且在CHF中下调，与K+电流记录一致。钙依赖性钾通道亚基（KCa1.1）mRNA和电流在LV成纤维细胞中比LA成纤维细胞表达少。用1 mmol/L的TEA抑制LA成纤维细胞K+电流或用紫杉醇抑制KCa1.1电流可增加增殖。
与对照相比，CHF中以及LA与LV相比，成纤维细胞Kv电流表达较小。LA与LV相比，KCa1.1电流更大。用TEA抑制Kv电流可增强成纤维细胞增殖，提示Kv电流可能起到抑制成纤维细胞增殖的作用，且CHF中Kv电流降低可能导致纤维化。成纤维细胞Kv电流重塑可能在心房颤动（AF）基质中起作用；调节成纤维细胞钾通道可能是预防纤维化和AF的新策略。
