Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways
Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways
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DOI：
10.1016/s0092-8674(02)00969-8
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发表时间：
2002-09-20
期刊：
影响因子：
64.5
通讯作者：
Penninger, JM
中科院分区：
文献类型：
--
作者：
Crackower, MA;Oudit, GY;Penninger, JM
PTEN/PI 3 K信号通路调节大量的基本细胞反应。我们发现，心肌细胞特异性失活的肿瘤抑制基因PTEN的结果在肥大，意想不到的是，在心脏收缩力急剧下降。对双突变小鼠的分析表明，心脏肥大和收缩力缺陷可以在遗传上解耦。PI 3 K α介导细胞大小的改变，而PI 3 K γ作为心肌收缩力的负调节剂。在机制上，PI 3 K γ抑制cAMP产生，并且可以通过阻断cAMP功能来逆转收缩过度。这些数据表明，PTEN在心肌细胞肥大和GPCR信号传导中具有重要的体内作用，并鉴定了PTEN-PI 3 K γ途径在调节心肌收缩性中的功能。
The PTEN/PI3K signaling pathway regulates a vast array of fundamental cellular responses. We show that cardiomyocyte-specific inactivation of tumor suppressor PTEN results in hypertrophy, and unexpectedly, a dramatic decrease in cardiac contractility. Analysis of double-mutant mice revealed that the cardiac hypertrophy and the contractility defects could be genetically uncoupled. PI3Kalpha mediates the alteration in cell size while PI3Kgamma acts as a negative regulator of cardiac contractility. Mechanistically, PI3Kgamma inhibits cAMP production and hypercontractility can be reverted by blocking cAMP function. These data show that PTEN has an important in vivo role in cardiomyocyte hypertrophy and GPCR signaling and identify a function for the PTEN-PI3Kgamma pathway in the modulation of heart muscle contractility.