PPAR-γ Activator Pioglitazone Prevents Age-Related Atrial Fibrillation Susceptibility by Improving Antioxidant Capacity and Reducing Apoptosis in a Rat Model
PPAR-γ Activator Pioglitazone Prevents Age-Related Atrial Fibrillation Susceptibility by Improving Antioxidant Capacity and Reducing Apoptosis in a Rat Model
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DOI：
10.1111/j.1540-8167.2011.02186.x
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发表时间：
2012-02-01
影响因子：
2.7
通讯作者：
Aonuma, Kazutaka
中科院分区：
文献类型：
--
作者：
Xu, Dongzhu;Murakoshi, Nobuyuki;Aonuma, Kazutaka
ppar - γ激活剂对大鼠心房颤动的上游治疗作用。简介：过氧化物酶体增殖物激活受体(PPAR)- γ是一种重要的脂质和葡萄糖代谢转录介质，在房颤（AF）中的体内作用仍有待充分阐明。我们研究了吡格列酮（ppar - γ激活剂）在AF大鼠体内模型中的作用。方法与结果：将Wistar大鼠分为3组：幼龄组、3月龄大鼠；老年组，9月龄大鼠给药；老年+Pio组，9月龄大鼠给予吡格列酮治疗。治疗4周后，比较3组30秒猝发起搏诱导的房颤持续时间、基因、蛋白表达及心房结构变化。采用电子自旋共振法测定心房氧化剂还原活性。老年组AF持续时间明显延长，老年+Pio组AF持续时间明显缩短。吡格列酮可逆转年龄引起的自由基还原活性下降。衰老+Pio大鼠抗氧化分子Sod2 （MnSOD）和Hspa1a（热休克70蛋白）基因和蛋白表达水平显著升高，NADPH氧化酶亚基p22（phox）和gp91（phox）基因和蛋白表达水平显著降低。吡格列酮治疗显著增加磷酸化的（p-） Akt，但显著降低p- erk1 /2和p- jnk。吡格列酮可显著恢复p-Bad，减少裂解的caspase-3和-9，表明吡格列酮可阻止年龄相关的凋亡信号通路增强。显微镜分析显示吡格列酮抑制年龄相关的组织学变化（间质纤维化和细胞凋亡）。结论：吡格列酮通过提高抗氧化能力和抑制线粒体凋亡信号通路抑制年龄相关性心律失常性心房重构和房颤延续。ppar - γ激活剂可能成为与年龄相关的房颤的一种新的上游治疗方法。（journal cardiovascular Electrophysiol, Vol. 23, pp. 209-217, 2012年2月）
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)