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Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

ABSTRACT: Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-?. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain.

SUBMITTER: Moon E

PROVIDER: S-EPMC4630407 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

Moon Eunjung E Han Jeong Eun JE Jeon Sejin S Ryu Jong Hoon JH Choi Ji Woong JW Chun Jerold J

Mediators of inflammation 20151020

Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral art ...[more]

PMID: 26576074

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Project description:RationaleCerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P1 modulation in stroke.ObjectiveTo address roles and mechanisms of engagement of endothelial cell S1P1 in the naive and ischemic brain and its potential as a target for cerebrovascular therapy.Methods and resultsUsing spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P1 in the mouse brain. With an S1P1 signaling reporter, we reveal that abluminal polarization shields S1P1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P1 signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P1 provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P1 supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P1-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion.ConclusionsThis study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P1 agonists.

Project description:ImportancePrevious studies have demonstrated the associations of daily high temperature with hospitalizations and mortality from ischemic stroke, but the hourly association of ambient heat and acute ischemic stroke (AIS) onset has been rarely examined.ObjectivesTo evaluate the association between hourly high ambient temperature and the onset of AIS.Design, setting, and participantsThis time-stratified case-crossover study was conducted using a nationwide registry that collects data from more than 200 stroke centers in China. Participants were adult patients with AIS who were hospitalized in the warm seasons between January 1, 2019, and December 31, 2021.ExposuresHourly temperature and single-hour temperature exposure lag up to 24 hours before the AIS onset (lag 0 hours to lag 24 hours).Main outcomes and measuresThe main outcome was onset of AIS. Associations between hourly mean temperatures and AIS onset were analyzed using conditional logistic regression integrated with the distributed lag nonlinear model. Stratification analyses were applied to examine potential association modifiers. Several sensitivity analyses were conducted to examine the robustness of the results.ResultsA total of 82 455 patients with AIS (mean [SD] age, 65.8 [11.9] years; 52 267 males [63.4%]) were included in the final analysis. A monotonically increasing risk of AIS onset was associated with higher temperatures. The excess AIS risk occurred immediately at lag 0 hours and persisted for 10 hours. Compared with the reference temperature (12.1 °C), the cumulative odds ratio (OR) over lag 0 to 10 hours of AIS onset associated with extremely high temperature (33.3 °C) was 1.88 (95% CI, 1.65-2.13) nationwide. The exposure-response curve was steeper in the north than in the south (OR, 1.80 [95% CI, 1.53-2.11] vs 1.57 [95% CI, 1.31-1.87]). The ORs were greater for males and patients with a history of dyslipidemia or atrial fibrillation, but the differences were not significant.Conclusions and relevanceResults of this study suggest that hourly heat exposure is associated with increased risk of AIS onset. This finding may benefit the formulation of public health strategies to reduce cerebrovascular risk associated with high ambient temperature under global warming.

Project description:BackgroundFibroblast activation protein α (FAP), a membrane glycoprotein with dipeptidyl-peptidase and collagenase properties, is expressed in atherosclerotic plaques and remodeling of the extracellular matrix based on fibrosis. Fibrosis is a main contributor of atrial cardiomyopathies. In acute MI, circulating FAP is associated with outcome. Here, we investigated the correlation of circulating FAP to echocardiographic parameters of atrial remodeling and neurological impairment in acute ischemic stroke.MethodsCirculating FAP plasma concentrations were determined by ELISA in 47 patients with acute stroke and 22 control patients without stroke. Echocardiography was performed in all participants. Laboratory analysis, National Institutes of Health Stroke Scale (NIHSS) scoring and prolonged Holter-ECG-monitoring were performed in all stroke patients.ResultsPatients with acute stroke had lower circulating FAP concentrations than the control cohort (92 ± 24 vs. 106 ± 22 ng/mL, P < 0.001). There was no difference between the circulating FAP concentration comparing stroke due to atrial fibrillation, embolic stroke of undetermined source (ESUS) or atherosclerotic origin. Septal atrial conduction time (sPA-TDI) and left atrial (LA) volume index to tissue Doppler velocity (LAVI/a') representing echocardiographic parameters of LA remodeling did not correlate with FAP concentrations (sPA-TDI: r = 0.123, p = 0.31; LAVI/a': r = 0.183, p = 0.132). Stroke severity as assessed by NIHSS inversely correlated with circulating FAP (r = -0.318, p = 0.04). FAP concentration had a fair accuracy for identifying stroke in the receiver operating characteristic (ROC) analysis (AUC = 0.710, 95% CI: 0.577-0.843). A FAP concentration of 101 ng/mL discriminated between presence and absence of stroke with a sensitivity of 72% and a specificity of 77%. Lower circulating FAP concentration was associated with cardio-cerebro-vascular events within 12 months after admission.ConclusionsOur study is the first to associate FAP with echocardiographic parameters of LA-remodeling and function. FAP did not correlate with sPA-TDI and LAVI/a'. However, FAP was associated with stroke, neurological impairment, and cardio-cerebral events within 12 months. Therefore, FAP might enable individualized risk stratification in ischemic stroke.

Dataset Information

Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

Publications

Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling.

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