The critical role of Akt in cardiovascular function.
The critical role of Akt in cardiovascular function.
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DOI：
10.1016/j.vph.2015.05.008
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发表时间：
2015-11
影响因子：
4
通讯作者：
Su Y
中科院分区：
文献类型：
--
作者：
Abeyrathna P;Su Y
Akt激酶是AGC激酶的一员，在细胞增殖、迁移、细胞生长和代谢等多种细胞功能中起重要作用。有三种已知的Akt亚型在心血管系统中发挥着关键和不同的作用。Akt活性在转录和翻译后水平受其上游调控通路的调控。β -catenin/Tcf-4、GLI1和Stat-3是目前已知的少数AKT基因的转录调控因子。苏氨酸308和丝氨酸473是Akt1的两个关键磷酸化位点。Akt在细胞膜上的易位促进了苏氨酸位点的PDK1磷酸化。丝氨酸位点被mTORC2磷酸化。Ack1、Src、PTK6、TBK1、IKBKE和IKKε是影响Akt活性的一些非典型通路。Akt与actin和Hsp90的蛋白-蛋白相互作用增加了Akt的活性，而Akt与其他蛋白（如CTMP和TRB3）的结合降低了Akt的活性。Akt对其下游靶点的作用决定了其在心血管过程中的功能，如细胞存活、生长、增殖、血管生成、血管松弛和细胞代谢。Akt通过caspase-9、YAP、Bcl-2和Bcl-x活性促进细胞存活。Akt抑制FoxO蛋白也通过转录机制提高细胞存活率。Akt通过mTORC1刺激细胞生长和增殖。Akt也增加VEGF分泌，介导eNOS磷酸化、血管舒张和血管生成。Akt可通过其下游靶点GSK3和GLUT4促进细胞代谢。Akt信号的改变在动脉粥样硬化、心肌肥厚、血管重构等心血管病理过程中发挥重要作用。一些Akt抑制剂已被开发并测试作为抗肿瘤药物。它们可能是治疗心血管疾病的潜在新疗法。
Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1. Translocation of Akt to the cell membrane facilitates PDK1 phosphorylation of the threonine site. The serine site is phosphorylated by mTORC2. Ack1, Src, PTK6, TBK1, IKBKE and IKKε are some of the non-canonical pathways which affect the Akt activity. Protein-protein interactions of Akt to actin and Hsp90 increase the Akt activity while Akt binding to other proteins such as CTMP and TRB3 reduces the Akt activity. The action of Akt on its downstream targets determines its function in cardiovascular processes such as cell survival, growth, proliferation, angiogenesis, vasorelaxation, and cell metabolism. Akt promotes cell survival via caspase-9, YAP, Bcl-2, and Bcl-x activities. Inhibition of FoxO proteins by Akt also increases cell survival by transcriptional mechanisms. Akt stimulates cell growth and proliferation through mTORC1. Akt also increases VEGF secretion and mediates eNOS phosphorylation, vasorelaxation and angiogenesis. Akt can increase cellular metabolism through its downstream targets GSK3 and GLUT4. The alterations of Akt signaling play an important role in many cardiovascular pathological processes such as atherosclerosis, cardiac hypertrophy, and vascular remodeling. Several Akt inhibitors have been developed and tested as anti-tumor agents. They could be potential novel therapeutics for the cardiovascular diseases.