期刊
CURRENT NEUROVASCULAR RESEARCH
卷 8, 期 3, 页码 220-235出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156720211796558069
关键词
Akt; apoptosis; Bad; caspase; endothelial; erythropoietin; FoxO3a; mitochondria; phosphatidylserine; sirtuin
资金
- American Diabetes Association
- American Heart Association (National)
- Bugher Foundation
- Janssen Neuroscience Award
- LEARN Foundation
- MI Life Sciences Challenge Award
- Nelson Foundation
- NIH NIEHS [P30 ES06639]
- NIH NIA
- NIH NINDS
- NIH ARRA
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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