Department of Laboratory Examination and Diagnostics, Department of Internal Medicine 1, and Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu, Japan.
Circ Arrhythm Electrophysiol. 2013 Apr;6(2):402-9. doi: 10.1161/CIRCEP.111.000104. Epub 2013 Feb 13.
We examined the hypothesis that leptin signaling contributes to the atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin II (AngII).
Eight-week-old male CL57/B6 (CNT) and leptin-deficient ob/ob mice (Ob) were subcutaneously infused with AngII (2.0 mg/kg per day). Two weeks later, transesophageal burst pacing and an electrophysiological study using isolated perfused hearts were performed. Left-atrial tissues were collected to determine interstitial fibrosis by Masson trichrome staining, and the expressions of mRNAs related to inflammatory profibrotic signals were assessed. Left-atrial fibroblasts were isolated from adult Sprague-Dawley and Zucker rats. The effects of leptin (100 ng/mL) or AngII (100 nmol/L) treatment were evaluated. In CNT-AngII mice, leptin expression in the left atrium was upregulated (P<0.01). Transesophageal burst pacing induced atrial fibrillation in 88% (7/8) of CNT-AngII mice, but not in Ob-AngII mice (0/8; P<0.01). In isolated perfused hearts, atrial fibrillation was induced only in CNT-AngII mice (4/6; 67%). Interatrial conduction time was prolonged in CNT-AngII mice (P<0.01), but not in Ob-AngII mice. The upregulation of collagen 1, collagen 3, transforming growth factor-β1, α-smooth muscle actin, MCP-1, F4/80, and RANTES mRNA, which was seen in CNT-AngII mice, was attenuated in Ob-AngII mice. In cultured Sprague-Dawley rat atrial fibroblasts, AngII treatment increased leptin expression (P<0.01). Addition of leptin increased transforming growth factor-β1, α-smooth muscle actin, MCP-1, and RANTES expressions in Sprague-Dawley rat atrial fibroblasts, but not in Zucker rat atrial fibroblasts.
Our results demonstrate for the first time that leptin signaling is essential for the development of atrial fibrosis and atrial fibrillation evoked by AngII.
我们研究了瘦素信号在血管紧张素 II（AngII）引起的心房纤维化和心房颤动（AF）中的作用假说。
8 周龄雄性 CL57/B6（CNT）和瘦素缺陷 ob/ob 小鼠（Ob）皮下输注 AngII（每天 2.0 mg/kg）。2 周后，进行经食管爆发性起搏和使用离体灌注心脏进行电生理研究。收集左心房组织，通过 Masson 三色染色确定间质纤维化，并评估与炎症致纤维化信号相关的 mRNA 表达。从成年 Sprague-Dawley 和 Zucker 大鼠中分离左心房成纤维细胞。评估瘦素（100ng/mL）或 AngII（100nmol/L）处理的影响。在 CNT-AngII 小鼠中，左心房中的瘦素表达上调（P<0.01）。经食管爆发性起搏诱导 88%（7/8）的 CNT-AngII 小鼠发生心房颤动，但在 Ob-AngII 小鼠中未发生（0/8；P<0.01）。在离体灌注心脏中，仅在 CNT-AngII 小鼠中诱导心房颤动（4/6；67%）。CNT-AngII 小鼠的房间隔传导时间延长（P<0.01），但 Ob-AngII 小鼠则不然。CNT-AngII 小鼠中胶原 1、胶原 3、转化生长因子-β1、α-平滑肌肌动蛋白、单核细胞趋化蛋白 1、F4/80 和 RANTES mRNA 的上调在 Ob-AngII 小鼠中减弱。在培养的 Sprague-Dawley 大鼠心房成纤维细胞中，AngII 处理增加了瘦素表达（P<0.01）。添加瘦素增加了 Sprague-Dawley 大鼠心房成纤维细胞中转化生长因子-β1、α-平滑肌肌动蛋白、单核细胞趋化蛋白 1 和 RANTES 的表达，但对 Zucker 大鼠心房成纤维细胞则没有。
我们的结果首次证明，瘦素信号对于 AngII 引起的心房纤维化和心房颤动的发展是必需的。
