Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China; Department of Cardiology, Minhang hospital, Ruijin Hospital Group, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
J Mol Cell Cardiol. 2013 Dec;65:1-8. doi: 10.1016/j.yjmcc.2013.09.016. Epub 2013 Oct 4.
It has been demonstrated that atrial remodeling contributes toward atrial fibrillation (AF) maintenance and angiotensin II (AngII) is involved in the pathogenesis of atrial remodeling. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been shown to inhibit atrial remodeling. However, the underlying mechanisms are poorly understood. In the present study we investigated the regulating effects of PPAR-γ agonist on AngII-induced atrial structural and electrical remodeling in vitro cellular models. The effects of pioglitazone on AngII-induced connective tissue growth factor (CTGF) expression and cell proliferation were assessed in primary-cultured mouse atrial fibroblasts. The influences of pioglitazone on AngII-induced L-type calcium channel (ICa-L) α1c expression and current density were evaluated in atrial myocytes (HL-1). Pioglitazone attenuated AngII-induced CTGF expression and proliferation in atrial fibroblasts, and pioglitazone also inhibited the expression or phosphorylation of AngII-induced transforming growth factor-β1 (TGF-β1), tumor necrosis factor receptor associated factor 6 (TRAF6), TGF-β-associated kinase 1 (TAK1) and Smad2/3. In HL-1 cells, pioglitazone suppressed AngII-induced ICa-L α1c expression and current density as well as CAMP responsive element binding protein (CREB) phosphorylation. Besides, pioglitazone inhibited AngII-induced production of AngII type I receptor (AT1R) and downregulation of PPAR-γ in both atrial fibroblasts and HL-1 cells. In conclusion, Pioglitazone suppresses AngII-induced CTGF expression and proliferation in atrial fibroblasts, which might be at least in part related with its inhibitory effects on TGF-β1/Smad2/3 and TGF-β1/TRAF6/TAK1 signaling pathways. Moreover, pioglitazone also attenuates AngII-induced ICa-L remodeling in HL-1 cells, which might be at least in part associated with its inhibitory effect on CREB phosphorylation. It is suggested that PPAR-γ agonist may have potential applications in preventing atrial remodeling.
已经证明，心房重构有助于维持心房颤动（AF），血管紧张素 II（AngII）参与了心房重构的发病机制。过氧化物酶体增殖物激活受体-γ（PPAR-γ）激动剂已被证明可抑制心房重构。然而，其潜在机制尚不清楚。本研究旨在探讨 PPAR-γ 激动剂对体外细胞模型中 AngII 诱导的心房结构和电重构的调节作用。在原代培养的小鼠心房成纤维细胞中评估吡格列酮对 AngII 诱导的结缔组织生长因子（CTGF）表达和细胞增殖的影响。在心房肌细胞（HL-1）中评估吡格列酮对 AngII 诱导的 L 型钙通道（ICa-L）α1c 表达和电流密度的影响。吡格列酮可减轻 AngII 诱导的心房成纤维细胞中 CTGF 的表达和增殖，并且吡格列酮还抑制 AngII 诱导的转化生长因子-β1（TGF-β1）、肿瘤坏死因子受体相关因子 6（TRAF6）、TGF-β 相关激酶 1（TAK1）和 Smad2/3 的表达或磷酸化。在 HL-1 细胞中，吡格列酮抑制 AngII 诱导的 ICa-Lα1c 表达和电流密度以及 cAMP 反应元件结合蛋白（CREB）磷酸化。此外，吡格列酮还抑制 AngII 诱导的心房成纤维细胞和 HL-1 细胞中 AT1R 的产生和 PPAR-γ 的下调。综上所述，吡格列酮抑制 AngII 诱导的心房成纤维细胞中 CTGF 的表达和增殖，这至少部分与其对 TGF-β1/Smad2/3 和 TGF-β1/TRAF6/TAK1 信号通路的抑制作用有关。此外，吡格列酮还可减轻 AngII 诱导的 HL-1 细胞中 ICa-L 的重构，这至少部分与它对 CREB 磷酸化的抑制作用有关。提示 PPAR-γ 激动剂可能具有预防心房重构的应用潜力。
