Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P<sub>3</sub> Receptor: Investigation Based on a New S1P<sub>3</sub> Receptor Antagonist

Murakami, Akira; Takasugi, Hiroshi; Ohnuma, Shinya; Koide, Yoshinobu; Sakurai, Akihiko; Takeda, Satoshi; Hasegawa, Takeshi; Sasamori, Jun; Konno, Takashi; Hayashi, Kenji; Watanabe, Yoshiaki; Mori, Koji; Sato, Yoshimichi; Takahashi, Atsuo; Mochizuki, Naoki; Takakura, Nobuyuki

doi:10.1124/mol.109.061481

Cited by 136 publications

(125 citation statements)

References 42 publications

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“…It is possible that receptors other than S1P1 may play a role in these effects. Murakami et al 46 showed that S1P influences VSMC contraction through S1P3 receptors, and Takashima et al 47 demonstrated that VSMC migration involves S1P2 receptors.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-Phosphate-Induced Inflammation Involves Receptor Tyrosine Kinase Transactivation in Vascular Cells

et al. 2011

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Abstract-Sphingosine-1-phosphate (S1P), a multifunctional phospholipid, regulates vascular cell function. Whether S1P influences vascular inflammatory responses, particularly in hypertension, is unclear. We tested the hypothesis that S1P is a proinflammatory mediator signaling through receptor tyrosine kinase transactivation and that responses are amplified in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats (SHRSPs), a model in which we demonstrated Edg1 (S1P1 receptor) to be a candidate gene for salt-sensitive hypertension. Vascular smooth muscle cell from Wistar-Kyoto rats and SHRSPs were studied. S1P receptor subtypes, S1P1 and S1P2, were similarly expressed in Wistar-Kyoto rats and SHRSPs. S1P induced phosphorylation of epidermal growth factor receptor and platelet-derived growth factor and activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, with amplified effects in SHRSPs versus Wistar-Kyoto rats. Inhibition of epidermal growth factor receptor and plateletderived growth factor (with AG1478 and AG1296, respectively) abolished S1P-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase in Wistar-Kyoto rats with variable effects in SHRSPs. Vascular smooth muscle cell inflammation was evaluated by expression of adhesion molecules and functional responses assessed by monocyte adhesion. S1P stimulated expression of intercellular adhesion molecule 1 and vascular cell adhesion protein 1 and promoted monocyte adhesion, particularly in SHRSP cells. S1P-mediated inflammation was blunted by AG1478 and AG1296 in SHRSP cells. VPC23019, a S1P1 receptor antagonist, inhibited S1P-induced mitogen-activated protein kinase phosphorylation, intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression, and monocyte adhesion.Our data indicate that molecular processes underlying vascular inflammation and cell adhesion in SHRSPs involve S1P/S1P1 receptors and phosphorylation of receptor tyrosine kinases. We identify a novel pathway linking S1P/S1P1 receptors to specific proinflammatory signaling pathways through epidermal growth factor receptor and platelet-derived growth factor transactivation, a process that is upregulated in SHRSPs. Such molecular events may contribute to vascular inflammation in hypertension. (Hypertension. 2011;57:809-818.) • Online Data Supplement Key Words: sphingosine-1-phosphate Ⅲ SHRSP Ⅲ EGFR Ⅲ PDGFR Ⅲ inflammation S phingosine 1-phosphate (S1P), an important structural entity of biological membranes, is also a bioactive lipid mediator involved in cell proliferation, survival, migration, and inflammation in various cell types, including vascular smooth muscle cells (VSMCs). 1-3 S1P serves as a ligand for a subset of G protein-coupled receptors, of which 5 mammalian S1P receptors (S1P1 through S1P5) have been identified. VSMCs, in culture, express S1P1, S1P2, and S1P3 receptors. 4 -8 The downstream targets of S1P signaling include adenylate cyclase, Ras, mitogen-activated protein kinase (MA...

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Section: Discussionmentioning

confidence: 99%

Sphingosine-1-Phosphate-Induced Inflammation Involves Receptor Tyrosine Kinase Transactivation in Vascular Cells

et al. 2011

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“…Although several types of Notch inhibitors are quite effective in preclinical models 21,48,49 , none of the clinical trials conducted so far has examined effectiveness 50 . This prompts us to encourage efforts to explore alternative/ additional approaches for targeting Notch.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of S1P were blocked by the S1PR3 antagonist TY52156 (ref. 21). Another antagonist CAY10444, which is structurally different from TY52156, also inhibited the S1P effect.…”

mentioning

confidence: 99%

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

et al. 2014

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Many tumours originate from cancer stem cells (CSCs), which is a small population of cells that display stem cell properties. However, the molecular mechanisms that regulate CSC frequency remain poorly understood. Here, using microarray screening in aldehyde dehydrogenase (ALDH)-positive CSC model, we identify a fundamental role for a lipid mediator sphingosine-1-phosphate (S1P) in CSC expansion. Stimulation with S1P enhances ALDH-positive CSCs via S1P receptor 3 (S1PR3) and subsequent Notch activation. CSCs overexpressing sphingosine kinase 1 (SphK1), an S1P-producing enzyme, show increased ability to develop tumours in nude mice, compared with parent cells or CSCs. Tumorigenicity of CSCs overexpressing SphK1 is inhibited by S1PR3 knockdown or S1PR3 antagonist. Breast cancer patient-derived mammospheres contain SphK1 þ /ALDH1 þ cells or S1PR3 þ /ALDH1 þ cells. Our findings provide new insights into the lipid-mediated regulation of CSCs via Notch signalling, and rationale for targeting S1PR3 in cancer.

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“…S1P 1 signaling reporter mice demonstrate receptor activation in endothelium under basal conditions, with enhanced S1P activation, dependent on plasma S1P, when systemic inflammation is induced (42). S1P 2 and S1P 3 are also expressed in vascular smooth muscle cells of resistance vessels and regulate vascular tone, especially during endothelial damage when plasma S1P accesses the medial smooth muscle cells (43)(44)(45)(46)(47). Alternatively, during injury or activation of vascular smooth muscle, enhanced activation/expression of sphingosine kinases could induce local S1P production within the vessel wall to influence vascular tone.…”

Section: S1p Metabolismmentioning

confidence: 99%

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

Proia¹,

Hla²

2015

J. Clin. Invest.

443

438

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IntroductionBioactive lipids, derived from metabolism of plasma membrane lipids, are important mediators of cellular communication in vertebrates. The appearance of bioactive lipid receptors in the vertebrate genomes (1) was coincident with the increased complexity of circulatory, immune, and nervous systems in evolution, suggesting that vertebrates began to use extracellular signaling of lipid mediators for the regulation of sophisticated organ systems. This Review will focus on the lysosphingolipid sphingosine-1-phosphate (S1P) and how the basic understanding of its metabolism, transport, and signaling functions has revealed its role in the pathogenesis of various diseases and allowed rational therapeutic strategies to advance. S1P metabolismSphingosine, the precursor substrate for the synthesis of S1P, is derived by the hydrolysis of ceramide during the sequential degradation of plasma membrane glycosphingolipids and sphingomyelin (refs. 2, 3, and Figure 1). Even though this occurs in various cell compartments, the bulk of sphingosine is generated by degradation in lysosomes. Indeed, the prominence of this lysosomal catabolism pathway is illustrated by the severity of the sphingolipidoses, a family of genetic disorders in which sphingolipid metabolites accumulate (4). The catabolically generated sphingosine is phosphorylated by either of two sphingosine kinases, SPHK1 and SPHK2, to produce S1P. SPHK1 is largely cytoplasmic and can acutely associate with the plasma membranes (5), phagosomes (6), and endosomal vesicles (7), whereas SPHK2 is present cytoplasmically but is predominately in the nucleus (8).While not strictly required for cellular viability (9), the formation of S1P is essential for organismal development (10). The viability of the single Sphk KO mice (10, 11) indicates that the isozymes can partially compensate for each other during development but have nonoverlapping functions. Once formed intracellularly, S1P takes one of three pathways (Figure 1). In one, the sphingosine moiety of S1P is recycled through ceramide synthesis after dephosphorylation by S1P-specific ER phosphatases, SGPP1 and SGPP2 (12, 13). In some mammalian cells, this pathway can account for greater than half of complex sphingolipid synthesis (14).In a second pathway, S1P is irreversibly degraded by S1P lyase, another ER-resident enzyme, into phosphoethanolamine and hexadecenal (15). This reaction facilitates transfer of substrate from the sphingolipid to the glycerolipid pathway via the conversion of hexadecenal by fatty aldehyde dehydrogenase to hexadecanoate, a precursor of palmitoyl-CoA (16), and by the utilization of phosphoethanolamine for phosphatidylethanolamine synthesis (17, 18).In the third pathway, intracellular S1P is released to the extracellular environment, a process that is highly efficient in rbc (19-21), platelets (22), and endothelial cells (19)(20)(21). A specific S1P transporter, SPNS2, is used in endothelial cells for S1P secretion (23). The precise secretion mechanism in rbc has not been established, but ...

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Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P₃ Receptor: Investigation Based on a New S1P₃ Receptor Antagonist

Cited by 136 publications

References 42 publications

Sphingosine-1-Phosphate-Induced Inflammation Involves Receptor Tyrosine Kinase Transactivation in Vascular Cells

Sphingosine-1-Phosphate-Induced Inflammation Involves Receptor Tyrosine Kinase Transactivation in Vascular Cells

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

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Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P3 Receptor: Investigation Based on a New S1P3 Receptor Antagonist

Cited by 136 publications

References 42 publications

Sphingosine-1-Phosphate-Induced Inflammation Involves Receptor Tyrosine Kinase Transactivation in Vascular Cells

Sphingosine-1-Phosphate-Induced Inflammation Involves Receptor Tyrosine Kinase Transactivation in Vascular Cells

Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

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Sphingosine 1-Phosphate (S1P) Regulates Vascular Contraction via S1P₃ Receptor: Investigation Based on a New S1P₃ Receptor Antagonist