Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance

Abstract

Background and Purpose-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 (1.7Ϯ0.2-fold) and activity (2.5Ϯ0.6-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. (Stroke. 2009;40:3342-3348.)

Junctional Protein Regulation by Sphingosine Kinase 2 Contributes to Blood–Brain Barrier Protection in Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance

“…Sphingosine-1-phosphate is produced by two sphingosine kinase (SphK) isoforms, SphK1 and SphK2, which often exhibit differing effects. Because only SphK2 protein levels and activity increased in cortical microvessels following HPC, and nonspecific SphK inhibition abrogated HPCs neuroprotective effects (Wacker et al, 2009), an isoformspecific contribution of SphK2 to ischemic tolerance was proposed.…”

Effects of normoxic and hypoxic exercise regimens on cardiac, muscular, and cerebral hemodynamics suppressed by severe hypoxia in humans

“…Animal studies have also indicated that hypoxic preconditioning reduced the volume of cerebral infarction and edema (41) and attenuated the loss of myocardial contractility (3) immediately after sublethal ischemic insult. Therefore, we speculate that increased O 2 delivery/utilization and resistance to acute hypoxic/ischemic stresses conferred by hypoxic interventions improves exercise performance and is effective for preventing and treating cerebrovascular/cardiovascular diseases.…”

Sphingolipids in cardiovascular and cerebrovascular systems: Pathological implications and potential therapeutic targets

“…The PI3K/Akt signaling cascade has been shown to play a key role in preventing apoptosis under hypoxic or ischemic conditions. Hypoxic preconditioning (HPC) has also been investigated in the contest of cerebral ischemia [105,108] . With respect to elucidating the molecular basis of preconditioning-induced tolerance, Yung et al [106] showed that hypoxic preconditioning significantly reduced infarct volume and improved neurological outcome in wild-type and SphK1-/-, but not in SphK2-/-mice.…”