PPARα/PGC-1α对阿霉素诱导的小鼠扩张型心肌病心力衰竭时心肌能量代谢的影响。
Effects of PPARα/PGC-1α on the myocardial energy metabolism during heart failure in the doxorubicin induced dilated cardiomyopathy in mice.
作者信息
Yang Yongyao, Zhang Hongming, Li Xiaoyan, Yang Tianhe, Jiang Qingan
机构信息
Department of Cardiology, Guizhou Provincial People's Hospital Guiyang 550002, China.
Department of Cardiology, The General Hospital of Jinnan Military Region Jinan 250031, China.
出版信息
Int J Clin Exp Med. 2014 Sep 15;7(9):2435-42. eCollection 2014.
OBJECTIVE
This study aims to investigate the effects and their mechanisms of PPARα and PGC-1α pathways in doxorubicin induced dilated cardiomyopathy in mice.
METHODS
The model of dilated cardiomyopathy (DCM) was established by injecting doxorubicin in mice. The 40 surviving mice were divided randomly into control group, doxorubicin model group, PPARα inhibitor and PPARα agonist group. The PPARα/PGC-1α proteins were detected. The size of adenine acid pool (ATP, ADP, AMP) and phosphocreatine (Pcr) in mitochondria were measured by HPLC. The ANT activity was detected by the atractyloside-inhibitor stop technique. The echocardiography and hemodynamic changes were detected in each group after PPARα inhibitor and PPARα agonist treatment for 2 weeks.
RESULTS
The DOX induced DCM model were successfully established. The expression of PPARα and PGC-1α protein level in normal group were significantly higher than that in DOX model group (P<0.05). Both the high-energy phosphate content and the transport activity of ANT were decreased in DOX group (P<0.05), and the hemodynamic parameters were disorder (P<0.01). Compared with Dox group, PPARα inhibitor intervention significantly reduce the expression of PPARα/PGC-1α, high-energy phosphate content in the mitochondria had no significant change (P>0.05), but the ANT transport activity of mitochondria decreased significantly (P<0.05), the left ventricular function decreased. On the other side, PPARα agonist intervention significantly increased the expression of PPARα and PGC-1α, improved transport activity of ANT, the hemodynamic parameters was ameliorated (P<0.05), but the high-energy phosphate content of mitochondria did not change significantly (P>0.05).
CONCLUSION
There was lower expression of PPARα and PGC-1α in DOC induced DCM in mice. Promotion of PPARα can improve myocardia energy metabolism and delay the occurrence of heart failure.
目的
本研究旨在探讨过氧化物酶体增殖物激活受体α（PPARα）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）信号通路在阿霉素诱导的小鼠扩张型心肌病中的作用及其机制。
方法
通过给小鼠注射阿霉素建立扩张型心肌病（DCM）模型。将40只存活小鼠随机分为对照组、阿霉素模型组、PPARα抑制剂组和PPARα激动剂组。检测PPARα/PGC-1α蛋白表达。采用高效液相色谱法测定线粒体中腺嘌呤酸池（ATP、ADP、AMP）和磷酸肌酸（Pcr）的含量。采用苍术苷抑制终止技术检测腺嘌呤核苷酸转位酶（ANT）活性。PPARα抑制剂和PPARα激动剂处理2周后，检测各组的超声心动图和血流动力学变化。
结果
成功建立了阿霉素诱导的DCM模型。正常组PPARα和PGC-1α蛋白表达水平显著高于阿霉素模型组（P<0.05）。阿霉素组高能磷酸含量和ANT转运活性均降低（P<0.05），血流动力学参数紊乱（P<0.01）。与阿霉素组相比，PPARα抑制剂干预显著降低PPARα/PGC-1α表达，线粒体高能磷酸含量无明显变化（P>0.05），但线粒体ANT转运活性显著降低（P<0.05），左心室功能下降。另一方面，PPARα激动剂干预显著增加PPARα和PGC-1α表达，改善ANT转运活性，血流动力学参数改善（P<0.05），但线粒体高能磷酸含量无明显变化（P>0.05）。
结论
在阿霉素诱导的小鼠DCM中，PPARα和PGC-1α表达较低。激活PPARα可改善心肌能量代谢，延缓心力衰竭的发生。
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