PPAR-γ Activator Pioglitazone Prevents Age-Related Atrial Fibrillation Susceptibility by Improving Antioxidant Capacity and Reducing Apoptosis in a Rat Model

PPAR-gamma Activator as Upstream Therapy for Atrial Fibrillation in Rat. Introduction: The in vivo role of peroxisome proliferator-activated receptor (PPAR)-gamma, an essential transcriptional mediator of lipid and glucose metabolism, in atrial fibrillation (AF) remains to be fully elucidated. We investigated the effects of pioglitazone, a PPAR-gamma activator, in an in vivo AF rat model. Methods and Results: We studied 3 groups of Wistar rats: young group, 3-month-old rats treated with vehicle; aged group, 9-month-old rats treated with vehicle; and aged+Pio group, 9-month-old rats treated with pioglitazone. After 4-week treatment, AF duration induced by 30-second burst pacing, gene and protein expressions, and atrial structural changes were compared between the 3 groups. Atrial oxidant reducing activity was measured by electron spin resonance method. AF duration was markedly prolonged in the aged group but significantly shortened in the aged+Pio group. Age-induced decrease in free radical reducing activity was reversed by pioglitazone. Gene and protein expression levels of antioxidant molecules Sod2 (MnSOD) and Hspa1a (heat shock 70 protein) were significantly enhanced, and p22(phox) and gp91(phox), two NADPH oxidase subunits, were significantly decreased in aged+Pio rats. Pioglitazone treatment significantly increased phosphorylated (p-) Akt but significantly reduced p-ERK1/2 and p-JNK. Pioglitazone significantly restored p-Bad and reduced cleaved caspase-3 and -9, indicating that pioglitazone prevented age-related enhancement of apoptotic signaling. Microscopic analysis revealed suppression of age-related histological changes (interstitial fibrosis and apoptosis) by pioglitazone. Conclusions: Pioglitazone inhibited age-related arrhythmogenic atrial remodeling and AF perpetuation by improving antioxidant capacity and inhibiting the mitochondrial apoptotic signaling pathway. PPAR-gamma activators could become a novel upstream therapy for age-related AF. (J Cardiovasc Electrophysiol, Vol. 23, pp. 209-217, February 2012)