卡维地洛对肥厚心肌能量代谢转换和结构重塑的作用研究

目的：研究卡维地洛对压力负荷性大鼠左室肥厚心肌中链脂酰辅酶A脱氢酶（MCAD）、肌型肉碱棕榈酰转移酶（M-CPT-I）和胶原结合蛋白（colligin）基因/蛋白表达变化的干预作用，阐明肥厚心肌能量代谢“胚胎型再演”和左室重塑的分子基础及卡维地洛心肌保护作用的可能机制。方法： 取健康雄性Wistar大鼠行腹主动脉缩窄（CAA）复制左室肥厚模型，取术后4周的大鼠随机分为腹主动脉缩窄（CAA）组和卡维地洛12周干预（CAR）组，设假手术（sham）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）CAA组大鼠左心室湿重/体重、平均动脉压高于sham组；血清和心肌游离脂肪酸含量大于sham组；左室心肌M-CPT-I、MCAD mRNA的表达低于sham组，而colligin基因和蛋白表达高于sham组；（2）卡维地洛治疗12周后能逆转上述各项指标的变化。结论： （1）肥厚心肌脂肪酸的利用减少，能量代谢呈“胚胎型再演”， M-CPT-I和MCAD基因表达下调，可能是导致能量代谢“胚胎型再演”的分子基础；（2）卡维地洛能增加线粒体脂肪酸氧化关键酶M-CPT-I和MCAD基因的表达，促进心肌对脂肪酸的利用，对肥厚心肌能量代谢“胚胎型再演”有抑制作用；（3）卡维地洛抑制压力负荷诱导的colligin蛋白表达，抑制心肌纤维化。对心肌能量代谢模式和心室重塑的保护作用可能是卡维地洛治疗心力衰竭的重要作用机制。

Role of carvedilol on energy metabolic reversion and remodeling of pressure overload-induced left ventricular hypertrophy in rats

AIM: To study changes of medium chain acyl-CoA dehydrogenase (MCAD), muscle carnitine palmitoyltransferase I (M-CPT-I) and colligin mRNA/protein expression, to elucidate molecular mechanism of the recapitulation of fetal energy metabolism and ventricular remodeling and the effects of carvedilol during the development of pressure overload-induced left ventricular hypertrophy in rats. METHODS: Male Wistar rats of hypertrophy induced by constriction of abdominal aorta （CAA） were randomized into 2 groups (n=12, each group): 4-week group (CAA4 weeks group) and 12-week carvedilol intervention group (CAR group). Additional rats (n=12) underwent abdominal cavity incision without ligation 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 expression of mRNA of M-CPT-I, MCAD and collagen binding protein (colligin) were investigated. The protein expression of colligin was analyzed by Western blotting in the experimental animals and sham operation.RESULTS: LVM/BW and MAP in CAA group were increased more significantly than in sham group. There were progressive increases in FAA both in blood serum and myocardium in CAA group than in sham group, accompanied with downregulation of gene expressions of M-CPT-I and MCAD and colligin mRNA/ protein upregulation in LV in CAA group, while changes of all of these parameters in CAR group were attenuated.CONCLUSIONS: (1) The down-regulated expression of cardiac FAO enzyme genes (M-CPT-I and MCAD) in the hypertrophied heart may be responsible for “the recapitulation of fetal energy metabolism” during the development of pressure overload-induced left ventricular hypertrophy in rats. (2) Carvedilol attenuates the reversion of the metabolic gene expression back towards fetal type. (3) Carvedilol is effective in regressing the left ventricular remodeling by inhibiting colligin protein expression. A molecular mechanism by which carvedilol may confer cardioprotective effects in heart failure may be, in part, via preserving of the adult metabolic gene regulation and regressing left ventricular remodeling.