Department of Neurology and Neurosciences, University of Medicine and Dentistry, New Jersey Medical School, Newark, New Jersey 07101, USA.
Curr Neurovasc Res. 2011 Aug 1;8(3):220-35. doi: 10.2174/156720211796558069.
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.
鉴于促红细胞生成素（EPO）在脑微血管内皮细胞（EC）中的细胞保护能力，以及 EC 在中枢神经系统中的重要作用，阐明 EPO 保护 EC 免受脑损伤的细胞途径至关重要。在这里，我们说明 EPO 依赖于 SIRT1（沉默交配型信息调节 2 同源物 1）在脑微血管 EC 中的调节，以在氧葡萄糖剥夺（OGD）期间促进细胞保护。SIRT1 的激活导致凋亡早期膜磷脂酰丝氨酸（PS）外翻和随后的 DNA 降解的抑制，成为 EPO 在 EC 中保护所必需的组成部分，因为 SIRT1 活性的抑制或通过基因沉默使其表达减少会破坏 EPO 在 OGD 期间支持的细胞存活。此外，EPO 促进 SIRT1 的亚细胞向核内转移，这对于 EPO 促进血管保护是必要的。EPO 通过 SIRT1 激活蛋白激酶 B（Akt1）和叉头转录因子 FoxO3a 的磷酸化和细胞质保留来避免细胞凋亡。通过 EPO 激活的 SIRT1 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、caspase 1 和 caspase 3 的激活。我们的工作确定了 EPO 在血管系统中的新途径，这些途径可以通过 Akt1、FoxO3a 磷酸化和易位、线粒体膜通透性、Bad 激活以及 caspase 1 和 3 在 EC 中的活性来调节 SIRT1 的活性，从而防止氧化应激期间的细胞凋亡损伤。
