title: Hypoxic preconditioning-induced cerebral ischemic tolerance: role of microvascular sphingosine kinase 2.
abstract: OBJECTIVE
  The importance of bioactive lipid signaling under physiological and pathophysiological conditions is progressively becoming recognized. The disparate distribution of sphingosine kinase (SphK) isoform activity in normal and ischemic brain, particularly the large excess of SphK2 in cerebral microvascular endothelial cells, suggests potentially unique cell- and region-specific signaling by its product sphingosine-1-phosphate. The present study sought to test the isoform-specific role of SphK as a trigger of hypoxic preconditioning (HPC)-induced ischemic tolerance.
  
  
  METHODS
  Temporal changes in microvascular SphK activity and expression were measured after HPC. The SphK inhibitor dimethylsphingosine or sphingosine analog FTY720 was administered to adult male Swiss-Webster ND4 mice before HPC. Two days later, mice underwent a 60-minute transient middle cerebral artery occlusion and at 24 hours of reperfusion, infarct volume, neurological deficit, and hemispheric edema were measured.
  
  
  RESULTS
  HPC rapidly increased microvascular SphK2 protein expression (1.7+/-0.2-fold) and activity (2.5+/-0.6-fold), peaking at 2 hours, whereas SphK1 was unchanged. SphK inhibition during HPC abrogated reductions in infarct volume, neurological deficit, and ipsilateral edema in HPC-treated mice. FTY720 given 48 hours before stroke also promoted ischemic tolerance; when combined with HPC, even greater (and dimethylsphingosine-reversible) protection was noted.
  
  
  CONCLUSIONS
  These findings indicate hypoxia-sensitive increases in SphK2 activity may serve as a proximal trigger that ultimately leads to sphingosine-1-phosphate-mediated alterations in gene expression that promote the ischemia-tolerant phenotype. Thus, components of this bioactive lipid signaling pathway may be suitable therapeutic targets for protecting the neurovascular unit in stroke.
authors: Department of Neurosurgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors: Bradley K
authors: BK
authors: Wacker
authors: Tae Sung
authors: TS
authors: Park
authors: Jeffrey M
authors: JM
authors: Gidday
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D002536:Cerebral Arteries / Q000378:metabolism* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D019194:Ischemic Preconditioning / Q000379:methods*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D012333:RNA, Messenger; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate