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

Journal of Cardiovascular Electrophysiology - Tập 23 Số 2 - Trang 209-217 - 2012
Dongzhu Xu1, Nobuyuki Murakoshi2, Miyako Igarashi2, Aki Hirayama3, Yoko Ito2, Yoshihiro Seo2, Hiroshi Tada2, Kazutaka Aonuma2
1Cardiovascular Division, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
2Cardiovascular Division, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba
3Center for Integrative Medicine, Tsukuba University of Technology, Tsukuba, Japan

Tóm tắt

PPAR‐γ Activator as Upstream Therapy for Atrial Fibrillation in Rat. Introduction: The in vivo role of peroxisome proliferator‐activated receptor (PPAR)‐γ, 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‐γ 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 p22phox and gp91phox, 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‐γ activators could become a novel upstream therapy for age‐related AF. J Cardiovasc Electrophysiol, Vol. 23, pp. 209‐217, February 2012)

Từ khóa


Tài liệu tham khảo

10.1161/01.CIR.98.10.946

10.1001/jama.1994.03510350050036

10.1016/j.mad.2008.02.010

10.1016/j.mad.2006.12.008

10.1161/01.CIR.104.2.174

10.1016/j.ijcard.2008.02.026

10.1016/S0735-1097(99)00382-4

10.1097/FJC.0b013e31817f9398

10.1161/01.CIR.101.22.2612

10.1161/01.CIR.0000145163.56529.D1

10.1016/j.jacc.2004.11.070

10.1016/j.jacc.2007.09.063

10.1016/j.ahj.2006.09.006

10.1038/347645a0

10.1016/S0140-6736(05)67528-9

10.1161/hc4601.099403

10.1161/01.CIR.0000039346.31538.2C

10.1016/j.hrthm.2007.12.010

Xu D, 2009, The effects of PPAR‐γ activator on atrial fibrillation in aged rat model, Heart Rhythm, 6, S172

10.1053/meta.2001.19415

10.1016/j.cardiores.2007.06.027

10.1161/ATVBAHA.107.155762

10.2337/diabetes.49.3.346

10.2337/db06-0268

10.1093/cvr/cvn019

10.1111/j.1540-8167.2009.01591.x

10.1152/ajprenal.00020.2004

10.1161/01.RES.0000183735.09871.61

10.1161/01.HYP.24.5.620

10.1016/j.athoracsur.2004.08.018

10.1139/H08-067

10.1002/jcp.21730

10.1016/j.neulet.2010.02.045

10.1152/ajpheart.00341.2006

10.1016/S0735-1097(00)00611-2

Thông tin
Thông tin xuất bản

Journal of Cardiovascular Electrophysiology

Tập 23 Số 2

209-217

Thông tin tác giả