Short periods of hypoxia upregulate sphingosine kinase 1 and increase vasodilation of arteries to Sphingosine 1-phosphate via S1P3

Alganga, H. S. F., Almabrouk, T. A.M. , Katwan, O. J., Daly, C. J. , Pyne, S., Pyne, N. J. and Kennedy, S. (2019) Short periods of hypoxia upregulate sphingosine kinase 1 and increase vasodilation of arteries to Sphingosine 1-phosphate via S1P3. Journal of Pharmacology and Experimental Therapeutics, 371(1), pp. 63-74. (doi:10.1124/jpet.119.257931) (PMID:31371480)

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Abstract

Aims: Sphingosine kinase (SK, isoforms SK1 and SK2) catalyses formation of the bioactive lipid, sphingosine 1-phosphate (S1P). This can be exported from cells and bind to S1P receptors to modulate vascular function. We investigated the effect of short-term hypoxia on SK1 expression and the response of arteries to S1P. Methods: SK1 expression in rat aortic and coronary artery endothelial cells was studied using immunofluorescence and confocal microscopy. Responses of rat aortic rings were studied using wire myography and reversible hypoxia induced by bubbling myography chambers with 95% N2:5% CO2. Inhibitors were added 30 mins before induction of hypoxia. Results: S1P induced an endothelium-dependent vasodilation via activation of S1P3 receptors and generation of nitric oxide (NO). Hypoxia significantly increased relaxation to S1P and this was attenuated by PF-543 (SK1 inhibitor) but not (R)-FTY720 methyl ether (ROMe; SK2 inhibitor). Hypoxia also increased vessel contractility to the thromboxane mimetic, U46619, which was further increased by PF-543 and ROMe. Hypoxia upregulated SK1 expression in aortic and coronary artery endothelial cells and this was blocked by PF-543 and SKi (SK1/2 inhibitor). The effects of the PF-543 and SKi were associated with increased proteasomal/lysosomal degradation of SK1. Conclusion: A short period of hypoxia increases the expression of SK1 which may generate S1P to oppose vessel contraction. Under hypoxic conditions, upregulation of SK1 is likely to lead to increased export of S1P from the cell and vasodilation via activation of endothelial S1P3 receptors. These data have significance for perfusion of tissue during episodes of ischaemia.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Katwan, Omar Jassim and Daly, Dr Craig and ALGANGA, Husam S F and Kennedy, Dr Simon and ALMABROUK, Tarek Ali Mohamed
Authors: Alganga, H. S. F., Almabrouk, T. A.M., Katwan, O. J., Daly, C. J., Pyne, S., Pyne, N. J., and Kennedy, S.
Subjects:R Medicine > RM Therapeutics. Pharmacology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Journal of Pharmacology and Experimental Therapeutics
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0022-3565
ISSN (Online):1521-0103
Published Online:01 August 2019

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