Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia
Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia
复制标题
DOI：
10.1093/emboj/cdg469
复制
发表时间：
2003-09-15
期刊：
影响因子：
11.4
通讯作者：
Alessi, DR
中科院分区：
文献类型：
--
作者：
Mora, A;Davies, AM;Alessi, DR
我们利用Cre/loxP技术产生了心肌中缺乏PDK1的mPDK1(-/-)小鼠。胰岛素不能激活PKB和S6K，也不能刺激mPDK1(-/-)小鼠心脏中6-磷酸果糖-2-激酶和2，6-二磷酸果糖的产生，这与PDK1介导的这些过程一致。所有mPDK1(-/-)小鼠在5至11周龄时突然死亡。MPDK1(-/-)动物的室壁变薄，心房和右室增大。此外，mPDK1(-/-)肌肉质量显著减少是由于心肌细胞体积的减少，而不是心肌细胞数量的减少，心力衰竭的标志物升高。这些结果表明mPDK1(-/-)小鼠死于心力衰竭，这一结论得到了超声心动图分析的支持。通过采用单细胞实验，我们发现mPDK1(-/-)小鼠的心肌细胞对缺氧明显更敏感。这些结果表明，PDK1信号网络在调节心脏活力和预防心力衰竭方面发挥着重要作用。他们还表明，PDK1途径的缺陷可能会导致人类心脏病的发生。
We employed Cre/loxP technology to generate mPDK1(-/-) mice, which lack PDK1 in cardiac muscle. Insulin did not activate PKB and S6K, nor did it stimulate 6-phosphofructo-2-kinase and production of fructose 2,6-bisphosphate, in the hearts of mPDK1(-/-) mice, consistent with PDK1 mediating these processes. All mPDK1(-/-) mice died suddenly between 5 and 11 weeks of age. The mPDK1(-/-) animals had thinner ventricular walls, enlarged atria and right ventricles. Moreover, mPDK1(-/-) muscle mass was markedly reduced due to a reduction in cardiomyocyte volume rather than cardiomyocyte cell number, and markers of heart failure were elevated. These results suggested mPDK1(-/-) mice died of heart failure, a conclusion supported by echocardiographic analysis. By employing a single-cell assay we found that cardiomyocytes from mPDK1(-/-) mice are markedly more sensitive to hypoxia. These results establish that the PDK1 signalling network plays an important role in regulating cardiac viability and preventing heart failure. They also suggest that a deficiency of the PDK1 pathway might contribute to development of cardiac disease in humans.