title: Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF, sphingosine kinase, and CCL2 signaling pathway.
abstract: The induction of ischemic tolerance by preconditioning provides a platform to elucidate endogenous mechanisms of stroke protection. In these studies, we characterize the relationship between hypoxia-inducible factor (HIF), sphingosine kinase 2 (SphK2), and chemokine (C-C motif) ligand 2 (CCL2) in models of hypoxic or pharmacological preconditioning-induced ischemic tolerance. A genetics-based approach using SphK2- and CCL2-null mice showed both SphK2 and CCL2 to be necessary for the induction of ischemic tolerance following preconditioning with hypoxia, the hypoxia-mimetic cobalt chloride, or the sphingosine-1-phosphate (S1P) agonist FTY720. A pharmacological approach confirmed the necessity of HIF signaling for all three preconditioning stimuli, and showed that the SphK/S1P pathway transduces tolerance via the S1P(1)  receptor. In addition, our data suggest significant cross-talk between HIF and SphK2-produced S1P signaling, which together act to up-regulate CCL2 expression. Overall, HIF, SphK, S1P, and CCL2 participate in a signaling cascade to induce the gene expression responsible for the stroke-tolerant phenotype established by hypoxic and FTY720 preconditioning. The identification of these common molecular mediators involved in signaling the genomic response to multiple preconditioning stimuli provides several targets for therapeutic manipulation.
authors.affiliation: Department of Neurosurgery, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wacker
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Perfater
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gidday
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000628:therapy; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017853:Phosphotransferases (Alcohol Group Acceptor); D019707:Receptors, Chemokine; D000099157:Sphingosine Kinase; C491768:Ccl2 protein, mouse; C471885:Cx3cr1 protein, mouse; C497443:Hif1a protein, mouse