Beneficial effects of pioglitazone on atrial structural and electrical remodeling in vitro cellular models
Beneficial effects of pioglitazone on atrial structural and electrical remodeling in vitro cellular models
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DOI：
10.1016/j.yjmcc.2013.09.016
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发表时间：
2013-12-01
影响因子：
5
通讯作者：
Zhang, Da-Dong
中科院分区：
文献类型：
--
作者：
Gu, Jun;Liu, Xu;Zhang, Da-Dong
心房重构是心房颤动（atrial fibrillation，AF）维持的重要因素，血管紧张素II（angiotensin 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-gamma）激动剂已被证明可抑制心房重构。然而，对潜在的机制知之甚少。在本研究中，我们研究了PPAR-gamma激动剂对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）上评价吡格列酮对AngII诱导的L型钙通道（ICa-L）α 1c表达和电流密度的影响。吡格列酮减弱了心房成纤维细胞中AngII诱导的CTGF表达和增殖，吡格列酮还抑制了AngII诱导的转化生长因子-β 1（TGF-β 1）、肿瘤坏死因子受体相关因子6（TRAF 6）、TGF-β相关激酶1（TAK 1）和Smad 2/3的表达或磷酸化。在HL-1细胞中，吡格列酮抑制AngII诱导的ICa-L α 1c表达和电流密度以及cAMP反应元件结合蛋白（CREB）磷酸化。此外，吡格列酮抑制AngII诱导的心房成纤维细胞和HL-1细胞中AngII I型受体（AT 1 R）的产生和PPAR-gamma的下调。总之，吡格列酮抑制AngII诱导的心房成纤维细胞CTGF表达和增殖，这可能至少部分与其对TGF-β 1/Smad 2/3和TGF-β 1/TRAF 6/TAK 1信号通路的抑制作用有关。此外，吡格列酮还减弱AngII诱导的HL-1细胞中的ICa-L重塑，这可能至少部分与其对CREB磷酸化的抑制作用有关。提示PPAR-gamma激动剂在预防心房重构中具有潜在的应用价值。(C)2013爱思唯尔有限公司保留所有权利。
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-gamma (PPAR-gamma) 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-gamma 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) alpha 1c 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-beta 1 (TGF-beta 1), tumor necrosis factor receptor associated factor 6 (TRAF6), TGF-beta-associated kinase 1 (TAK1) and Smad2/3. In HL-1 cells, pioglitazone suppressed AngII-induced ICa-L alpha 1c 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-gamma 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-beta 1/Smad2/3 and TGF-beta 1/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-gamma agonist may have potential applications in preventing atrial remodeling. (C) 2013 Elsevier Ltd. All rights reserved.