PDK1 plays a critical role in regulating cardiac function in mice and human
PDK1 plays a critical role in regulating cardiac function in mice and human
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DOI：
10.3760/cma.j.issn.0366-6999.2010.17.014
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发表时间：
2010-09-05
影响因子：
6.1
通讯作者：
Yang Zhong-zhou
中科院分区：
文献类型：
--
作者：
Di Ruo-min;Feng Qiu-ting;Yang Zhong-zhou
背景PDK 1是一种在哺乳动物发育过程中起关键作用的必需蛋白激酶。缺乏PDK 1的小鼠在E9.5时导致多种异常和胚胎死亡。为了阐明PDK 1在心脏中的作用，我们研究了不同生长时期心脏中缺乏PDK 1的小鼠的心脏表型和人衰竭心脏中PDK 1信号的改变（flox/flox）：α-MHC-Cre小鼠，在出生时特异性删除心肌中的PDK 1，和他莫昔芬诱导的心脏特异性PDK 1敲除小鼠（PDK 1（flox/flox）：MerCreMer小鼠），其中响应于他莫昔芬治疗，心肌中的PDK 1被删除。结果PDK 1（flox/flox）：α-MHC-Cre小鼠分别于5周龄和10周龄死于心力衰竭。PDK 1（flox/flox）-MerCreMer小鼠在8周大时开始他莫昔芬治疗后5至21周死于心力衰竭。结论PDK 1信号网络参与了小鼠心脏存活和功能的调节，可能也参与了人类心力衰竭的发病过程。中华医学杂志2010;123（17）：2358-2363
Background PDK1 is an essential protein kinase that plays a critical role in mammalian development. Mouse lacking PDK1 leads to multiple abnormalities and embryonic lethality at E9.5. To elucidate the role of PDK1 in the heart, we investigated the cardiac phenotype of mice that lack PDK1 in the heart in different growth periods and the alteration of PDK1 signaling in human failing heart.Methods We employed Cre/loxP system to generate PDK1(flox/flox): alpha-MHC-Cre mice, which specifically deleted PDK1 in cardiac muscle at birth, and tamoxifen-inducible heart-specific PDK1 knockout mice (PDK1(flox/flox):MerCreMer mice), in which PDK1 was deleted in myocardium in response to the treatment with tamoxifen. Transmural myocardial tissues from human failing hearts and normal hearts were sampled from the left ventricular apex to analyze the activity of PDK1/Akt signaling pathways by Western blotting.Results PDK1(flox/flox): alpha-MHC-Cre mice died of heart failure at 5 and 10 weeks old. PDK1(flox/flox)-MerCreMer mice died of heart failure from 5 to 21 weeks after the initiation of tamoxifen treatment at 8 weeks old. We found that expression levels of PDK1 in human failing heart tissues were significantly decreased compared with control hearts.Conclusion Our results suggest that PDK1 signaling network takes part in regulating cardiac viability and function in mice, and may be also involved in human heart failure disease. Chin Med J 2010;123(17):2358-2363