Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress.
Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress.
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DOI：
10.2174/156720211796558069
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发表时间：
2011-08-01
影响因子：
2.1
通讯作者：
Maiese K
中科院分区：
文献类型：
--
作者：
Hou J;Wang S;Shang YC;Chong ZZ;Maiese K
鉴于红细胞生成素（EPO）对脑微血管内皮细胞（EC）的细胞保护能力以及EC在中枢神经系统中的宝贵作用，阐明EPO保护EC免受脑损伤的细胞途径势在必行。在这里，我们说明，EPO依赖于SIRT 1（沉默交配型信息调节器2同源物1）在脑微血管内皮细胞的调制，以促进细胞保护过程中的氧-葡萄糖剥夺（OGD）。SIRT 1激活导致OGD期间细胞凋亡早期膜磷脂酰丝氨酸（PS）外化和随后的DNA降解的抑制，成为EPO保护EC的必要组成部分，因为通过基因沉默抑制SIRT 1活性或减少其表达会消除OGD期间EPO支持的细胞存活。此外，EPO促进SIRT 1的亚细胞运输到细胞核，这是EPO促进血管保护所必需的。EPO通过SIRT 1通过激活蛋白激酶B（Akt 1）和叉头转录因子FoxO 3 a的磷酸化和胞质滞留来避免细胞凋亡。SIRT 1通过EPO激活还利用线粒体途径来防止线粒体去极化、细胞色素c释放以及Bad、半胱天冬酶1和半胱天冬酶3激活。我们的工作确定了EPO在血管系统中的新途径，该途径可以控制SIRT 1的活性，以防止氧化应激期间EC中Akt 1，FoxO 3a磷酸化和运输，线粒体膜通透性，Bad激活以及caspase 1和3活性的凋亡损伤。
Given the cytoprotective ability of erythropoietin (EPO) in cerebral microvascular endothelial cells (ECs) and the invaluable role of ECs in the central nervous system, it is imperative to elucidate the cellular pathways for EPO to protect ECs against brain injury. Here we illustrate that EPO relies upon the modulation of SIRT1 (silent mating type information regulator 2 homolog 1) in cerebral microvascular ECs to foster cytoprotection during oxygen-glucose deprivation (OGD). SIRT1 activation which results in the inhibition of apoptotic early membrane phosphatidylserine (PS) externalization and subsequent DNA degradation during OGD becomes a necessary component for EPO protection in ECs, since inhibition of SIRT1 activity or diminishing its expression by gene silencing abrogates cell survival supported by EPO during OGD. Furthermore, EPO promotes the subcellular trafficking of SIRT1 to the nucleus which is necessary for EPO to foster vascular protection. EPO through SIRT1 averts apoptosis through activation of protein kinase B (Akt1) and the phosphorylation and cytoplasmic retention of the forkhead transcription factor FoxO3a. SIRT1 through EPO activation also utilizes mitochondrial pathways to prevent mitochondrial depolarization, cytochrome c release, and Bad, caspase 1, and caspase 3 activation. Our work identifies novel pathways for EPO in the vascular system that can govern the activity of SIRT1 to prevent apoptotic injury through Akt1, FoxO3a phosphorylation and trafficking, mitochondrial membrane permeability, Bad activation, and caspase 1 and 3 activities in ECs during oxidant stress.
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影响因子：
2.1
作者：
Chong ZZ;Maiese K
通讯作者：
Maiese K
影响因子：
5.3
作者：
Bakker, Walbert J.;van Dijk, Thamar B.;von Lindern, Marieke
通讯作者：
von Lindern, Marieke
影响因子：
4.8
作者：
Balan, Vitaly;Miller, Gregory S.;Tzivion, Guri
通讯作者：
Tzivion, Guri
影响因子：
7.3
作者：
Chong, ZZ;Kang, JQ;Maiese, K
通讯作者：
Maiese, K
影响因子：
37.8
作者：
Chong, ZZ;Kang, JQ;Maiese, K
通讯作者：
Maiese, K