title: Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats.
abstract: OBJECTIVE
  Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injuries.
  
  
  METHODS
  Rat pups underwent common carotid artery ligation followed by either 150min (severe model) or 100min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) was used to examine their roles on BBB permeability.
  
  
  RESULTS
  Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability.
  
  
  CONCLUSIONS
  rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α's effects as a prodeath or prosurvival signal were influenced by the severity of HI injury.
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, China; Department of Anesthesiology and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Xudan
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Desislava Met
authors.initials: DM
authors.lastname: Doycheva
authors.affiliation: Department of Anesthesiology and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, China. Electronic address: zryanmin@zju.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. Electronic address: johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism* / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D042461:Vascular Endothelial Growth Factor A; C465398:SESN2 protein, human; D000084622:Sestrins; C583887:Sesn2 protein, rat
keywords: Brain edema; Hi 95; Hypoxia inducible factor1; Neonatal hypoxic-ischemic encephalopathy