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 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 pharmacologic approach confirmed the necessity of HIF signaling for all three preconditioning stimuli, and showed the SphK/S1P pathway to transduce tolerance via the S1P1 receptor. Additionally, our data suggest significant cross-talk between HIF and SphK2-produced S1P signaling, which together act to upregulate 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.

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…Neuron-specific deficiency of HIF-1a increases brain injury and mortality in a mouse model of transient focal cerebral ischemia, implicating a neuroprotective function of HIF-1a (Baranova et al, 2007). Moreover, hypoxic preconditioning induces stroke tolerance in mice via HIF-1a signaling Wacker et al, 2012). Other studies, however, show that deletion or inhibition of HIF-1a resulted in reduced brain damage after ischemic stroke or hypoxic conditions, suggesting a detrimental role of HIF-1a (Helton et al, 2005;Chen et al, 2009a;Cheng et al, 2014).…”

Embolic Middle Cerebral Artery Occlusion from Innominate Artery Stenosis: Successful Mechanical Recanalisation

“…The concept of ischemic preconditioning in stroke patients normally utilizes "remote" ischemia, normally of the limb [15]. However, experimental strategy target i.e., hypoxia-inducible factor, sphingosine kinase 2 and chemokine ligand 2 to induce a gene expression responsible for the stroke-tolerant phenotype [16]. Also, IAS might have promoted the development of pial collateral network by upregulation of vascular endothelial growth factor, all was which might have contributed to the excellent outcome [17].…”

Cerebral Ischemic Preconditioning: the Road So Far…

“…A mechanism has recently been proposed in which preconditioning with cobalt or hypoxia promotes SPK-2 catalytic activity, producing the signaling molecule sphingosine-1-phosphate (SIP). SIP upregulates chemokine (C-C motif) ligand 2 (CCL2) to bring about tolerance post-ischemia [84].…”