Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia
Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia
复制标题
10 号染色体上的磷酸酶和张力蛋白同源物响应缺氧的调节。
DOI：
10.1152/ajpheart.00929.2011
复制
发表时间：
2012-05-01
影响因子：
4.8
通讯作者：
Ye, Yumei
中科院分区：
文献类型：
--
作者：
Qian, Jinqiao;Ling, Shukuan;Ye, Yumei
10号染色体上的磷酸酶和张力蛋白同源物（PTEN）在肥大和癌细胞生长期间下调，导致促存活Akt途径的激活。然而，心肌细胞暴露于缺氧后的PTEN调节仍不清楚。我们探讨了PTEN在心肌缺氧/缺血反应中的作用。我们验证了PTEN是转录激活因子2（ATF-2）的转录靶点，并且通过p38/ATF-2信号通路正调控。因此，缺氧诱导的ATF-2和PTEN磷酸化上调被显性失活突变体p38逆转。抑制心肌细胞中的PTEN减弱缺氧诱导的细胞死亡和凋亡。心脏特异性敲除PTEN导致Akt和叉头框O 1（叉头转录因子）磷酸化增加，缺血再灌注损伤动物梗死面积有限，并改善永久性冠状动脉闭塞后左心室功能恶化和重塑。此外，Bim、FASL和半胱天冬酶的激活与PTEN激活偶联，所有这些都被PTEN抑制减弱。总之，心肌细胞特异性条件性PTEN缺失在缺血再灌注损伤的体内模型中限制了心肌梗死面积，并在慢性永久性冠状动脉结扎模型中减弱了不良重塑。
Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxia-induced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation.