A potential link between peroxisome proliferator-activated receptor signalling and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy
A potential link between peroxisome proliferator-activated receptor signalling and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy
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DOI：
10.1093/cvr/cvp183
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发表时间：
2009-10-01
影响因子：
10.8
通讯作者：
Coirault, Catherine
中科院分区：
文献类型：
--
作者：
Djouadi, Fatima;Lecarpentier, Yves;Coirault, Catherine
致心律失常性右心室心肌病 (ARVC) 的特点是右心室 (RV) 发生主要纤维脂肪替代。我们假设过氧化物酶体增殖物激活受体（PPAR）信号的变化导致 ARVC 中心肌脂肪堆积和收缩功能障碍。采用实时定量逆转录酶聚合酶链反应和蛋白质印迹法评估 PPAR α 和 γ 及其两个下游靶基因中链酰基辅酶 A 脱氢酶的心脏表达 (MCAD) 和磷酸烯醇丙酮酸羧激酶 (PEPCK) - 在五名对照者和五名 ARVC 患者的 RV 和左心室 (LV) 中。体外运动测定用于分析肌球蛋白的功能特性。在 RV 中，ARVC 中的滑动速度比对照组低近两倍，而 ARVC 和 LV 中非衰竭心肌之间的速度值降低了 10%。在对照组中，右心室中的 PPAR α 和 MCAD mRNA 和蛋白质水平高于左心室。在 ARVC 中，RV 和 LV 中 PPAR α 和 MCAD mRNA 和/或蛋白的表达均降低。来自 ARVC 的 RV 的特征还在于 PPAR γ 途径的显着激活，PPAR γ mRNA 和蛋白质的增加（分别为 500 % 和 270%，每个 P < 0.001）以及 PEPCK 基因的诱导证明了这一点。相反，与对照相比，ARVC心脏的左心室PPARγ调节通路的表达没有变化。ARVC与右心室中PPARα和PPARγ信号通路的主要紊乱有关，这可能导致细胞内脂质超载和严重的肌球蛋白功能障碍。
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by major fibro-fatty replacement of the right ventricle (RV). We hypothesized that changes in peroxisome proliferator-activated receptor (PPAR) signalling contributed to myocardium fatty accumulation and contractile dysfunction in ARVC.Real-time quantitative reverse transcriptase-polymerase chain reaction and western blotting were used to assess cardiac expression of PPAR alpha and gamma and two of their downstream target genes-medium-chain acyl-CoA dehydrogenase (MCAD) and phosphoenolpyruvate carboxykinase (PEPCK)-in both RV and left ventricle (LV) from five controls and five ARVC patients. In vitro motility assays were used to analyse functional properties of myosin. In the RV, sliding velocity was nearly two-fold lower in ARVC than in controls, whereas a 10% reduction in velocity values was noted between ARVC and non-failing myocardium in the LV. In controls, PPAR alpha and MCAD mRNA and protein levels were higher in the RV compared with the LV. In ARVC, the expression of PPAR alpha and MCAD mRNA and/or proteins was decreased in both RV and LV. RV from ARVC was also characterized by a dramatic activation of the PPAR gamma pathway, as attested by the increase in PPAR gamma mRNA and protein (500 and 270%, respectively, each P < 0.001) and by the induction of PEPCK gene. In contrast, the LV of ARVC heart exhibited no changes in the expression of the PPAR gamma regulatory pathway compared with control.ARVC is associated with major disturbances in the PPAR alpha and PPAR gamma signalling pathway in the RV that may contribute to intracellular lipid overload and severe myosin dysfunction.