Chen Yu, Surinkaew Sirirat, Naud Patrice, Qi Xiao-Yan, Gillis Marc-Antoine, Shi Yan-Fen, Tardif Jean-Claude, Dobrev Dobromir, Nattel Stanley
Department of Medicine and Research Center Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Quebec, H1T 1C8 Canada.
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6 Canada.
Cardiovasc Res. 2017 Mar 1;113(3):310-320. doi: 10.1093/cvr/cvx004.
Left-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis.
LA-remodelling was studied in dogs with heart failure (HF) induced by ventricular tachypacing (VTP, 240 bpm), and in mice with left-ventricular (LV) dysfunction due to myocardial infarction (MI). The selective STAT-3 inhibitor S3I-201 was administered to fibroblasts in vitro or mice in vivo (10 mg/kg/d, osmotic mini-pump). HF-dogs developed LA-selective fibrosis and AF-susceptibility at 1-week VTP. The mRNA-expression of platelet-derived growth factor (PDGF, a JAK-STAT activator) isoforms A, C and D, as well as JAK2, increased in LA fibroblasts from 1-week VTP. HF upregulated protein-expression of PDGF-receptor-β and phosphorylated (activated) signal transducer and activator of transcription 3 (STAT3) in LA. PDGF-AB stimulation of LA fibroblasts increased PDGFR-α, STAT3 and phosphorylated-STAT3 expression, as well as collagen-1 and fibronectin-1 protein secretion (by 1.6- to 20-fold), with smaller changes in LV fibroblasts. Phosphorylated-STAT3 and collagen upregulation were suppressed by the JAK2 inhibitor AG-490, PDGF receptor inhibitor AG1296 and STAT3-inhibitor SI3-201. In vivo S3I-201 treatment of MI-mice attenuated LA-fibrosis, LA-dilation and P-wave duration changes versus vehicle-control.
HF activates the LA JAK-STAT system and enhances PDGF-signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA-fibrogenesis and might be a potential target for LA-fibrosis prevention.
左心房（LA）纤维化是许多心房颤动（AF）基质的一个重要特征。JAK-STAT系统参与心脏重塑，但其在AF中的作用尚不清楚。在此，我们研究了AF模型中JAK-STAT的变化及其对LA纤维化的潜在影响。
在通过心室快速起搏（VTP，240次/分钟）诱导心力衰竭（HF）的犬以及因心肌梗死（MI）导致左心室（LV）功能障碍的小鼠中研究LA重塑。将选择性STAT-3抑制剂S3I-201体外给予成纤维细胞或体内给予小鼠（10mg/kg/天，渗透微型泵）。HF犬在VTP 1周时出现LA选择性纤维化和AF易感性。来自VTP 1周的LA成纤维细胞中血小板衍生生长因子（PDGF，一种JAK-STAT激活剂）异构体A、C和D以及JAK2的mRNA表达增加。HF上调了LA中PDGF受体-β和磷酸化（激活）信号转导子和转录激活子3（STAT3）的蛋白表达。LA成纤维细胞的PDGF-AB刺激增加了PDGFR-α、STAT3和磷酸化-STAT3的表达，以及胶原蛋白-1和纤连蛋白-1的蛋白分泌（增加1.6至20倍），LV成纤维细胞的变化较小。JAK2抑制剂AG-490、PDGF受体抑制剂AG1296和STAT3抑制剂SI3-201抑制了磷酸化-STAT3和胶原蛋白的上调。与载体对照相比，MI小鼠体内S3I-201治疗减轻了LA纤维化、LA扩张和P波持续时间变化。
HF激活LA JAK-STAT系统并增强PDGF信号传导。JAK-STAT抑制降低了PDGF刺激对犬成纤维细胞的促纤维化作用，同时减轻了MI后小鼠体内的LA纤维化和重塑，提示JAK/STAT途径有助于LA纤维化形成，可能是预防LA纤维化的潜在靶点。
