PPARα/PGC-1α在阿霉素扩张型心肌病小鼠心肌组织中的表达及作用

目的:探讨过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptorsα,PPARα)及过氧化物酶体增殖物活化受体协同刺激因子1α(peroxisome proliferator activated receptor coactivator 1 alpha,PGC-1α)在阿霉素(doxorubicin,DOX)诱导扩张型心肌病小鼠心肌中的变化及其对心肌能量代谢及心功能的影响。方法:选取小鼠40只,分为正常对照组、单纯阿霉素模型组、PPARα抑制剂组和PPARα激动剂组。除正常对照组外,其余小鼠采用阿霉素诱导建立扩张型心肌病模型,检测其中PPARα及PGC-1α蛋白的表达,PPARα抑制剂组和PPARα激动剂组在造模前分别采用PPARα抑制剂及激动剂对小鼠预处理2周,高效液相层析法(high-performance liquid chromatography,HPLC)测量线粒体内腺苷酸含量,[3H]-ADP(氚标记二磷酸腺苷)掺入法检测线粒体膜腺苷酸转运体(adenine nucleotide translocator,ANT)转运活性,并利用超声心动图检测各组心脏结构及心功能。结果:成功建立阿霉素诱导的扩张型心肌病模型,PPARα及PGC-1α蛋白在模型组中表达明显低于正常组(P0.05),线粒体内高能磷酸盐含量和线粒体转运活性明显降低(P0.05),心功能显著下降,血流动力学指标紊乱(P0.05);与模型组比较,PPARα抑制剂预处理2周后,可显著降低PPARα/PGC-1α表达,线粒体内高能磷酸盐含量及线粒体ANT转运活性显著降低(P0.05),心功能恶化;而予PPARα激动剂预处理干预2周,上调PPARα/PGC-1α蛋白表达同时,虽然线粒体内高能磷酸盐含量未发现有显著变化,但其可改善阿霉素心肌病大鼠线粒体ANT转运活性,超声心动图显示对心腔大小及心功能有改善作用(P0.05)。结论:在阿霉素诱导扩张性心肌病中,PPARα/PGC-1α对ANT的活性起重要调控作用,激活PPARα/PGC-1α可减轻阿霉素心肌损伤。

Role of PPARα/PGC-1α in doxorubicin induced mouse dilated cardio-myopathy

AIM: To investigate the changes of peroxisome proliferator-activated receptors (PPAR)α/peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1α) in doxorubicin (DOX) induced dilated cardiomyopathy (DCM) and its effect on the energy metabolism and myocardial function in mice. METHODS: Forty mice were randomly divided into 4 groups: control group, DOX group, PPARα inhibitor group and PPARα agonist group. The DCM model was established by injection of DOX. The protein levels of PPARα/PGC-1α were detected. The PPARα inhibitor and PPARα agonist were used 2 weeks beforeinjection of DOX. The contents of adenine acid and phosphocreatine (Pcr) in the mitochondria were measured by high-performance liquid chromatography (HPLC). The ANT activity was analyzed by the atractyloside-inhibitor stop technique. The changes of the echocardiography and hemodynamics were also observed. RESULTS: DOX induced DCM model was successfully established. The protein levels of PPARα and PGC-1α in control group were significantly higher than those in DOX group (P<0.05). Both of the high-energy phosphate contents and the transport activity of ANT were decreased in DOX group (P<0.05), and the hemodynamic parameters were disordered (P<0.01). Compared with DOX group, PPARα inhibitor pre-treatment significantly reduced the PPARα/PGC-1α expression. Meanwhile, high-energy phosphate contents in the mitochondria and the ANT transport activity of the mitochondria decreased, as well as the left ventricular function (P<0.05). On the other hand, PPARα agonist significantly increased the expression of PPARα and PGC-1α, and improved the transport activity of ANT. In addition, the hemodynamic parameters were ameliorated, but the high-energy phosphate contents of the mitochondria did not significantly change. CONCLUSION: PPARα/PGC-1α plays an important role in the regulation of ANT transport activity in dilated cardiomyopathy induced by DOX, and the activation of PPARα/PGC-1α has protective effects on the DCM induced by DOX.