Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan-induced diabetic rabbits.

Abstract

Recent evidence indicates that peroxisome proliferator-activated receptor (PPAR)-γ activators exert anti-inflammatory and antioxidant actions. However, the underlying mechanisms by which these agents prevent atrial remodeling in diabetes are not completely elucidated. We sought to investigate the potential effects of pioglitazone, a PPAR-γ activator, on atrial remodeling and atrial fibrillation (AF) inducibility in diabetic rabbits. Alloxan-induced diabetic rabbits were randomly divided into three groups: diabetes only, diabetes treated with low-dose pioglitazone (4mg/day/kg), or diabetes treated with high-dose pioglitazone (8mg/day/kg) (n=24 for each group). A total of 24 healthy rabbits served as controls. Eight weeks later, hemodynamic, echocardiographic, and electrophysiological parameters were recorded. Left atrial whole-cell patch-clamp studies, histological examination, and Western blot analysis were also performed. In the DM group (6/8 vs 1/8, P<.05), higher AF inducibility, increased amount of fibrosis, lower INa , and higher ICaL were observed in the DM group compared to controls. Western blot analysis showed that DM increased the expression of extracellular signal-regulated kinase 2 (ERK2), phosphorylation ERK, transforming growth factor beta-1, Toll-like receptor 4, nuclear factor-κB p50, and heat-shock protein 70. All of these electrophysiological, histological, ion current density, and protein expression changes were all reduced by pioglitazone. Pioglitazone attenuates diabetes-induced structural and electrophysiological remodeling in the atria, thereby reducing the vulnerability to AF.