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

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.