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Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis
Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediat...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052545/ http://dx.doi.org/10.3390/ph4010117 |
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author | Okamoto, Yasuo Wang, Fei Yoshioka, Kazuaki Takuwa, Noriko Takuwa, Yoh |
author_facet | Okamoto, Yasuo Wang, Fei Yoshioka, Kazuaki Takuwa, Noriko Takuwa, Yoh |
author_sort | Okamoto, Yasuo |
collection | PubMed |
description | Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and cell-cell adhesion in a variety of cell types via five members of S1P-specific high-affinity G protein-coupled receptors (S1P(1)-S1P(5)). Among them, S1P(1), S1P(2) and S1P(3) are major receptor subtypes which are widely expressed in various tissues. Available evidence suggest that S1P and HDL-bound S1P exert atheroprotective effects including inhibition of leukocyte adhesion and stimulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) through the activation of G(i) signaling pathway via S1P(3) and probably S1P(1), although there is still controversy. FTY720, the phosphorylation product of which is a high-affinity agonist for all S1P receptors except S1P(2) and act as an immunosuppressant by downregulating S1P(1) on lymphocytes, inhibits atherosclerosis in LDL receptor-null mice and apoE-null mice through the inhibition of lymphocyte and macrophage functions and probably stimulation of EC functions, without influencing plasma lipid concentrations. In contrast to S1P(1) and S1P(3), S1P(2) facilitates atherosclerosis by activating G(12/13)-Rho-Rho kinase (ROCK) in apoE-null mice. S1P(2) mediates transmigration of monocytes into the arterial intima, oxidized LDL accumulation and cytokine secretion in monocyte-derived macrophages, and eNOS inhibition and cytokine secretion in ECs through Rac inhibition, NF-κB activation and 3′-specific phosphoinositide phosphatase (PTEN) stimulation downstream of G(12/13)-Rho-ROCK. Systemic long-term administration of a selective S1P(2)-blocker remarkably inhibits atherosclerosis without overt toxicity. Thus, multiple S1P receptors positively and negatively regulate atherosclerosis through multitudes of mechanisms. Considering the essential and multi-faceted role of S1P(2) in atherogenesis and the impact of S1P(2) inactivation on atherosclerosis, S1P(2) is a particularly promising therapeutic target for atherosclerosis. |
format | Online Article Text |
id | pubmed-4052545 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-40525452014-06-11 Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis Okamoto, Yasuo Wang, Fei Yoshioka, Kazuaki Takuwa, Noriko Takuwa, Yoh Pharmaceuticals (Basel) Review Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and cell-cell adhesion in a variety of cell types via five members of S1P-specific high-affinity G protein-coupled receptors (S1P(1)-S1P(5)). Among them, S1P(1), S1P(2) and S1P(3) are major receptor subtypes which are widely expressed in various tissues. Available evidence suggest that S1P and HDL-bound S1P exert atheroprotective effects including inhibition of leukocyte adhesion and stimulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) through the activation of G(i) signaling pathway via S1P(3) and probably S1P(1), although there is still controversy. FTY720, the phosphorylation product of which is a high-affinity agonist for all S1P receptors except S1P(2) and act as an immunosuppressant by downregulating S1P(1) on lymphocytes, inhibits atherosclerosis in LDL receptor-null mice and apoE-null mice through the inhibition of lymphocyte and macrophage functions and probably stimulation of EC functions, without influencing plasma lipid concentrations. In contrast to S1P(1) and S1P(3), S1P(2) facilitates atherosclerosis by activating G(12/13)-Rho-Rho kinase (ROCK) in apoE-null mice. S1P(2) mediates transmigration of monocytes into the arterial intima, oxidized LDL accumulation and cytokine secretion in monocyte-derived macrophages, and eNOS inhibition and cytokine secretion in ECs through Rac inhibition, NF-κB activation and 3′-specific phosphoinositide phosphatase (PTEN) stimulation downstream of G(12/13)-Rho-ROCK. Systemic long-term administration of a selective S1P(2)-blocker remarkably inhibits atherosclerosis without overt toxicity. Thus, multiple S1P receptors positively and negatively regulate atherosclerosis through multitudes of mechanisms. Considering the essential and multi-faceted role of S1P(2) in atherogenesis and the impact of S1P(2) inactivation on atherosclerosis, S1P(2) is a particularly promising therapeutic target for atherosclerosis. MDPI 2011-01-04 /pmc/articles/PMC4052545/ http://dx.doi.org/10.3390/ph4010117 Text en © 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Review Okamoto, Yasuo Wang, Fei Yoshioka, Kazuaki Takuwa, Noriko Takuwa, Yoh Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis |
title | Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis |
title_full | Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis |
title_fullStr | Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis |
title_full_unstemmed | Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis |
title_short | Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis |
title_sort | sphingosine-1-phosphate-specific g protein-coupled receptors as novel therapeutic targets for atherosclerosis |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052545/ http://dx.doi.org/10.3390/ph4010117 |
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