Premium
Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF , sphingosine kinase, and CCL 2 signaling pathway
Author(s) -
Wacker Bradley K.,
Perfater Jennifer L.,
Gidday Jeffrey M.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12047
Subject(s) - sphingosine kinase , sphingosine , sphingosine 1 phosphate , sphingosine kinase 1 , ischemic preconditioning , hypoxia inducible factors , signal transduction , pharmacology , agonist , lipid signaling , microbiology and biotechnology , chemistry , receptor , biology , medicine , biochemistry , ischemia , gene
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 ( CCL 2) in models of hypoxic or pharmacological preconditioning‐induced ischemic tolerance. A genetics‐based approach using SphK2‐ and CCL 2‐null mice showed both SphK2 and CCL 2 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 FTY 720. 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 CCL 2 expression. Overall, HIF , SphK, S1P, and CCL 2 participate in a signaling cascade to induce the gene expression responsible for the stroke‐tolerant phenotype established by hypoxic and FTY 720 preconditioning. The identification of these common molecular mediators involved in signaling the genomic response to multiple preconditioning stimuli provides several targets for therapeutic manipulation.