过氧化物酶体增殖剂活化受体α信号通路对肥厚心肌能量代谢胚胎型再演的调控作用

Peroxisome proliferator-activated receptor α signaling in the control of the recapitulation of fetal energy metabolism during the development of pressure overload induced left ventricular hypertrophy in rats

目的 研究压力负荷性大鼠左室肥厚心肌中链脂酰辅酶A(MCAD)、肌型肉碱棕榈酰转移酶 (M CPT I)和过氧化物酶体增殖剂活化受体α(PPARα)基因 /蛋白的表达变化 ,阐明肥厚心肌能量代谢“胚胎型再演”的分子机制和PPARα的调控作用。方法 取健康雄性Wistar大鼠行腹主动脉缩窄 (CAA)制成左室肥厚模型 ,随机分为 2周组 (CAA2W组 )、4周组 (CAA4W组 )、8周组 (CAA8W 组 )、16周组 (CAA16W组 ) ,设立假手术组作为对照 ,以上每组均为 12只 ,观察各组大鼠各项指标的变化。结果 ( 1)与假手术组比较 ,CAA各组大鼠左心室湿重 /体重、平均动脉压升高 ,4周后左室舒张末压、左室收缩压、+dp/dtmax开始升高 ,术后 8周 -dp/dtmax开始降低 ,以CAA16W组最显著 ,而CAA各组右心室湿重 /体重无明显变化 ;( 2 )CAA各组大鼠血清和心肌游离脂肪酸含量进行性增加 ;( 3)CAA各组大鼠左室心肌M CPT I、MCADmRNA的表达逐渐下降 ;( 4 )CAA各组大鼠左室心肌PPARα基因表达下调 ,术后 8周PPARα蛋白水平开始下调 ,以CAA16W组最显著。结论 ( 1)在腹主动脉缩窄所致的肥厚心肌模型中 ,血清和心肌游离脂肪酸含量增加 ,表明脂肪酸的利用减少 ,心肌能量代谢呈“胚胎型再演” ,调控脂肪酸氧化关键酶 (M CPT I和MCAD)的基因表达下调 ,可能是?

Objective To study changes of medium chain acyl CoA dehydrogenase (MCAD), muscle carnitine palmitoyltransferase I (M CPT I )and peroxisome proliferator activated receptor α (PPARα)mRNA/protein expressions, to elucidate molecular mechanism of the recapitulation of fetal energy metabolism and the effects of PPARα signaling during the development of pressure overload induced left ventricular hypertrophy in rats Methods Male wistar rats of left ventricular hypertrophy induced by coarctation of abdominal aorta(CAA) were randomized into 4 groups of 12 each: 2 week group (CAA 2W group), 4 week group (CAA 4W group), 8 week group (CAA 8W group), and 16 week group (CAA 16W group) Additional rats( n =12) underwent abdominal incision without ligation of aorta to serve as age matched sham operated controls (SH) Hemodynamics, ventricular remodeling parameters and free fatty acid(FFA)both in blood serum and myocardium were measured RT PCR analysis of the expressions of mRNA of M CPT I , MCAD and PPARα were investigated The protein expression of PPARα were analyzed by Western blot in the experimental animals and SH Results Compared with SH group, LVM/BW and MAP were significantly increased in all CAA groups, LVEDP, LVSP were increased in CAA 4W , CAA 8W and CAA 16W groups,+dp/dt max were increased in CAA 4W while -dp/dt max were decreased in CAA 8W and CAA 16W groups, changes of all of these parameters in CAA 16W group were most significant Changes of RVW/BW are not significant in all CAA groups There were progressive increase of FFA both in blood serum and myocardium in all CAA groups, accompanied with gradual downregulation of gene expressions of M CPT I, MCAD and PPARα in LV, while protein expression of PPARα began to be decreased till 8 week after operation Conclusions (1) Accumulation of FFA both in blood serum and myocardium which indicates the decreasing of fatty acid utilization during the development of pressure overload induced left ventricular hypertrophy in rats The down regulated expression of cardiac fatty acid oxidase(FAO) genes (M CPT I and MCAD) in the hypertrophied heart may be responsible for 'the recapitulation of fetal energy metabolism' (2) Reduced activity of PPARα is in parallel with down regulation of expression of cardiac FAO genes and fatty acid utilization in hypertrophied heart PPARα signaling may play a major role in energy metabolism during the development of pressure overload induced left ventricular hypertrophy