JOURNAL ARTICLE

Beneficial effects of pioglitazone on atrial structural and electrical remodeling in vitro cellular models

Jun Gu, Xu Liu, Quan-Xing Wang, Meng Guo, Fang Liu, Zhi-Ping Song, Da-Dong Zhang
Journal of Molecular and Cellular Cardiology 2013, 65: 1-8
24100253
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.

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