Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice
Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice
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磷酸肌醇依赖性激酶 1 和 mTORC2 协同维持小鼠产后心脏生长和心脏功能
DOI：
10.1128/mcb.00144-14
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发表时间：
2014-03
影响因子：
5.3
通讯作者：
Yang, Zhongzhou
中科院分区：
文献类型：
--
作者：
Sun, Haixiang;Li, Xinli;Hu, Yali;Yang, Zhongzhou
摘要蛋白激酶Akt在心脏功能中起着关键作用，它通过磷酸化苏氨酸308（T308）和丝氨酸473（S473）而被激活。虽然磷酸肌醇依赖性激酶1（PDK1）负责Akt T308磷酸化，但心脏中Akt S473磷酸化的激酶的身份仍然存在争议。在这里，我们通过删除心脏中的Rictor来破坏mTOR复合物2（mTORC2），并发现正常的心脏生长和功能。Rictor缺失导致Akt S473磷酸化显著降低，但Akt T308磷酸化增强，表明高水平的Akt T308磷酸化维持Akt活性和心脏功能。心脏中Pdk1的缺失导致Akt S473磷酸化显著增强，而Rictor的去除抑制了Akt S473磷酸化，导致Pdk1缺陷小鼠的扩张型心肌病（DCM）恶化和心力衰竭加速。此外，我们发现通过缺失Pten或化学抑制PTEN来增加Akt S473磷酸化可以逆转Pdk1缺陷小鼠的DCM和心力衰竭。对来自人类DCM患者的心脏样本的研究显示了与小鼠模型相似的变化。这些结果表明，PDK1和mTORC2协同促进出生后心脏生长并维持出生后小鼠的心脏功能。
ABSTRACT The protein kinase Akt plays a critical role in heart function and is activated by phosphorylation of threonine 308 (T308) and serine 473 (S473). While phosphoinositide-dependent kinase 1 (PDK1) is responsible for Akt T308 phosphorylation, the identities of the kinases for Akt S473 phosphorylation in the heart remain controversial. Here, we disrupted mTOR complex 2 (mTORC2) through deletion of Rictor in the heart and found normal heart growth and function. Rictor deletion caused significant reduction of Akt S473 phosphorylation but enhanced Akt T308 phosphorylation, suggesting that a high level of Akt T308 phosphorylation maintains Akt activity and heart function. Deletion of Pdk1 in the heart caused significantly enhanced Akt S473 phosphorylation that was suppressed by removal of Rictor, leading to worsened dilated cardiomyopathy (DCM) and accelerated heart failure in Pdk1-deficient mice. In addition, we found that increasing Akt S473 phosphorylation through deletion of Pten or chemical inhibition of PTEN reversed DCM and heart failure in Pdk1-deficient mice. Investigation of heart samples from human DCM patients revealed changes similar to those in the mouse models. These results demonstrated that PDK1 and mTORC2 synergistically promote postnatal heart growth and maintain heart function in postnatal mice.
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DOI：
10.2741/e207
发表时间：
2010-06
期刊：
Frontiers in bioscience
影响因子：
--
作者：
Z. Chang;Qi Xiao;Qiuting Feng;Zhongzhou Yang
通讯作者：
Z. Chang;Qi Xiao;Qiuting Feng;Zhongzhou Yang
DOI：
10.1093/med/1.1.med-9780198520771-div1-289
发表时间：
2005
期刊：
--
影响因子：
--
作者：
H. Schultheiss;D. Fairweather;A. Caforio;F. Escher;R. Hershberger;S. Lipshultz;Peter P. Liu;A. Matsumori;A. Mazzanti;J. Mcmurray;S. Priori
通讯作者：
H. Schultheiss;D. Fairweather;A. Caforio;F. Escher;R. Hershberger;S. Lipshultz;Peter P. Liu;A. Matsumori;A. Mazzanti;J. Mcmurray;S. Priori
影响因子：
16
作者：
Loewith, R;Jacinto, E;Hall, MN
通讯作者：
Hall, MN
影响因子：
9.2
作者：
Williams, MR;Arthur, JSC;Alessi, DR
通讯作者：
Alessi, DR
影响因子：
81.5
作者：
N. Lakdawala;Jeffery Winterfield;B. Funke
通讯作者：
N. Lakdawala;Jeffery Winterfield;B. Funke