Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure
Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure
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DOI：
10.1016/j.hrthm.2007.12.010
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发表时间：
2008-03-01
期刊：
影响因子：
5.5
通讯作者：
Murohara, Toyoaki
中科院分区：
文献类型：
--
作者：
Shimano, Masayuki;Tsuji, Yukiomi;Murohara, Toyoaki
背景：过氧化物酶体增殖物激活受体-γ(PPAR-γ)激动剂吡格列酮在体外可拮抗血管紧张素II的作用，并具有抗炎和抗氧化作用。目的观察吡格列酮对充血性心力衰竭兔致心律失常心房结构重构的影响，并与血管紧张素II 1型受体阻滞剂坎地沙坦的作用进行比较。方法采用兔心力衰竭模型，在没有或联合应用吡格列酮、坎地沙坦及联合用药的情况下，以380~400次/分的速度进行4周的心动过速实验。结果除单纯室性心动过速(房颤)兔(房颤平均持续时间：8.0+/-1.4秒)外，非起搏对照组均未诱发出持续时间超过2秒的房颤(房颤)。吡格列酮缩短房颤持续时间(3.5+/-0.2秒，P<；0.05)和减弱心房结构重构，在心房间激动时间(50+/-2ms比41.2毫秒，P<；0.05)和心房纤维化(16.8%+/-0.8%比10.9%+/-0.7%，P<；0.05；对照1.6%+/-0.2%)方面显著缩短，与坎地沙坦(房颤持续时间：3.0+/-0.2秒；激活时间44+/-2ms；纤维化9.4%+/-0.6%)。吡格列酮和坎地沙坦均可降低转化生长因子-β1、肿瘤坏死因子-α，并激活细胞外信号调节蛋白激酶的表达，但均不影响p38-激酶或c-jun氨基末端激酶的激活。联合应用吡格列酮和坎地沙坦的疗效与单独应用吡格列酮或坎地沙坦的疗效无显著差异。结论吡格列酮可减轻充血性心力衰竭所致的心房结构重构和房颤的促进作用，其作用与坎地沙坦相似。PPAR-γ可能成为治疗房颤的潜在靶点。
BACKGROUND The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator pioglitazone antagonizes angiotensin II actions and possesses anti-inflammatory and antioxidant properties in vitro. There is evidence that pioglitazone improves ventricular remodeling in some experimental models.OBJECTIVE The purpose of this study was to assess the effects of pioglitazone on arrhythmogenic atria[ structural remodeling versus the effects of the angiotensin II type 1 receptor blocker candesartan in a rabbit model of congestive heart failure.METHODS Rabbits subjected to ventricular tachypacing at 380 to 400 bpm for 4 weeks in the absence and presence of treatment with pioglitazone, candesartan, and combined pioglitazone and candesartan were assessed by electrophysiologic study, atrial fibrosis measurements, and cytokine expression analyses.RESULTS Atrial fibrillation (AF) tasting longer than 2 seconds was induced in no nonpaced controls but in all ventricular tachypacing-only rabbits (mean duration of AF: 8.0 +/- 1.4 seconds). Pioglitazone reduced the duration of AF (3.5 +/- 0.2 seconds, P < .05) and attenuated atrial structural remodeling, with significant reductions in interatrial activation time (50 +/- 2 ms vs 41 2 ms, P < .05) and atrial fibrosis (16.8% +/- 0.8% vs 10.9% +/- 0.7%, P < .05; control 1.6% +/- 0.2%), effects comparable to those of candesartan (duration of AF: 3.0 +/- 0.2 seconds; activation time 44 +/- 2 ms; fibrosis: 9.4% +/- 0.6%). Both piogtitazone and candesartan reduced transforming growth factor-beta 1, tumor necrosis factor-alpha, and activated extracellular signat-regulated kinase expression similarly, but neither affected p38-kinase or c-Jun N-terminal kinase activation. The effects of combined pioglitazone and candesartan therapy were not significantly different from the effects of piogtitazone or candesartan atone.CONCLUSION Pioglitazone can attenuate congestive heart failure-induced atrial structural remodeling and AF promotion, with effects similar to those of candesartan. PPAR-gamma may be a potential therapeutic target for human AF.