sphingosine-kinase and Atherosclerosis

Sphingosine-1-phosphate (S1P) is a pleiotropic sphingophospholipid generated from the phosphorylation of sphingosine by sphingosine kinases (SPHKs). S1P has been experimentally demonstrated to modulate an array of cellular processes such as cell proliferation, cell survival, cell invasion, vascular maturation, and angiogenesis by binding with any of the five known G-protein-coupled sphingosine 1 phosphate receptors (S1P1-5) on the cell surface in an autocrine as well as a paracrine manner. Recent studies have shown that the S1P receptors (S1PRs) and SPHKs are the key targets for modulating the pathophysiological consequences of various debilitating diseases, such as cancer, sepsis, rheumatoid arthritis, ulcerative colitis, and other related illnesses. In this article, we recapitulate these novel discoveries relative to the S1P/S1PR axis, necessary for the proper maintenance of health, as well as the induction of tumorigenic, angiogenic, and inflammatory stimuli that are vital for the development of various diseases, and the novel therapeutic tools to modulate these responses in oral biology and medicine.

Topics: Animals; Atherosclerosis; Autoimmune Diseases; Cell Proliferation; Gene Expression Regulation, Enzymologic; GTP-Binding Protein alpha Subunits; GTP-Binding Protein Regulators; Humans; Lymphatic Metastasis; Lysophospholipids; Mandibular Condyle; Neovascularization, Pathologic; Neurogenic Inflammation; Periodontitis; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

The bioactive lipid sphingosine-1-phosphate (S1P) fulfils manifold tasks in the immune system acting in auto- and/or paracrine fashion. This includes regulation of apoptosis, migration and proliferation. Upon its generation by sphingosine kinases from plasma membrane sphingolipids, S1P can either act as a second messenger within cells or can be released from cells to occupy a family of specific G-protein-coupled receptors (S1P1-5). This diversity is reflected by the impact of S1P on macrophage biology and function. Over the last years it became apparent that the sphingosine kinase/S1P/S1P-receptor signalling axis in macrophages might play a central role in the pathogenesis of inflammatory diseases such as atherosclerosis, asthma, rheumatoid arthritis and cancer. Here, we summarize the current knowledge of the function of S1P in macrophage biology and discuss potential implications for pathology.

Topics: Animals; Arthritis, Rheumatoid; Asthma; Atherosclerosis; Humans; Inflammation; Lysophospholipids; Macrophage Activation; Macrophages; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Receptors, G-Protein-Coupled; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

Pharmacological interference with sphingolipid metabolizing enzymes promises to provide novel ways to modulate cellular pathways relevant in multiple diseases. In this review, we focus on two sphingolipid signaling molecules, sphingosine-1-phosphate (S1P) and ceramide, as they are involved in cell fate decisions (survival vs. apoptosis) and in a wide range of pathophysiological processes. For S1P, we will discuss sphingosine kinases and S1P lyase as the enzymes which are crucial for its production and degradation, respectively, emphasizing the potential therapeutic usefulness of inhibitors of these enzymes. For ceramide, we will concentrate on acid sphingomyelinase, and critically review the substantial literature which implicates this enzyme as a worthwhile target for pharmacological inhibitors. It will become clear that the task to validate these enzymes as drug targets is not finished and many questions regarding the therapeutic usefulness of their inhibitors remain unanswered. Still this approach holds promise for a number of totally new therapies, and, on the way, detailed insight into sphingolipid signaling pathways can be gained.

Topics: Aldehyde-Lyases; Anaphylaxis; Animals; Apoptosis; Atherosclerosis; Bacterial Infections; Ceramides; Cyclooxygenase 2; Dendritic Cells; Drug Design; Enzyme Inhibitors; Humans; Immunologic Factors; Leukocytes; Lysophospholipids; Macrophages; Mast Cells; Neoplasms; Neovascularization, Pathologic; Phosphotransferases (Alcohol Group Acceptor); RNA, Small Interfering; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingosine

The lysosphingolipid sphingosine 1-phosphate (S1P) is a component of HDL. Findings from a growing number of studies indicate that S1P is a mediator of many of the cardiovascular effects of HDL, including the ability to promote vasodilation, vasoconstriction, and angiogenesis, protect against ischemia/reperfusion injury, and inhibit/reverse atherosclerosis. These latter cardioprotective effects are being shown to involve the S1P-mediated suppression of inflammatory processes, including reduction of the endothelial expression of monocyte and lymphocyte adhesion molecules, decreased recruitment of polymorphonuclear cells to sites of infarction, and blocking of cardiomyocyte apoptosis after myocardial infarction. This review article summarizes the evidence that S1P as a component of HDL serves to regulate vascular cell and lymphocyte behaviors associated with cardiovascular (patho)physiology.

Topics: Animals; Atherosclerosis; ATP-Binding Cassette Transporters; Cardiovascular System; Cell Movement; Cystic Fibrosis Transmembrane Conductance Regulator; Endothelial Cells; Humans; Immunologic Factors; Lipoproteins, HDL; Lysophospholipids; Muscle, Smooth, Vascular; Phosphotransferases (Alcohol Group Acceptor); Reperfusion Injury; Signal Transduction; Sphingosine; Vasoconstriction; Vasodilation

Sphingolipids have emerged as molecules whose metabolism is regulated leading to generation of bioactive products including ceramide, sphingosine, and sphingosine-1-phosphate. The balance between cellular levels of these bioactive products is increasingly recognized to be critical to cell regulation; whereby, ceramide and sphingosine cause apoptosis and growth arrest phenotypes, and sphingosine-1-phosphate mediates proliferative and angiogenic responses. Sphingosine kinase is a key enzyme in modulating the levels of these lipids and is emerging as an important and regulated enzyme. This review is geared at mechanisms of regulation of sphingosine kinase and the coming to light of its role in disease.

Topics: Animals; Atherosclerosis; Ceramides; Diabetes Mellitus; Enzyme Activation; Humans; Inflammation; Lysophospholipids; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Formation of foam cells as a result of excess lipid accumulation by macrophages is a pathological hallmark of atherosclerosis. Fingolimod (FTY720) is an immunosuppressive agent used in clinical settings for the treatment of multiple sclerosis and has been reported to inhibit atherosclerotic plaque development. However, little is known about the effect of FTY720 on lipid accumulation leading to foam cell formation. In this study, we investigated the effects of FTY720 on lipid accumulation in murine macrophages. FTY720 treatment reduced lipid droplet formation and increased the expression of ATP-binding cassette transporter A1 (ABCA1) in J774 mouse macrophages. FTY720 also enhanced the expression of liver X receptor (LXR) target genes such as FASN, APOE, and ABCG1. In addition, FTY720-induced upregulation of ABCA1 was abolished by knockdown of sphingosine kinase 2 (SphK2) expression. Furthermore, we found that FTY720 treatment induced histone H3 lysine 9 (H3K9) acetylation, which was lost in SphK2-knockdown cells. Taken together, FTY720 induces ABCA1 expression through SphK2-mediated acetylation of H3K9 and suppresses lipid accumulation in macrophages, which provides novel insights into the mechanisms of action of FTY720 on atherosclerosis.

Topics: Animals; Atherosclerosis; ATP Binding Cassette Transporter 1; Cholesterol; Fingolimod Hydrochloride; Foam Cells; Liver X Receptors; Mice; Phosphotransferases (Alcohol Group Acceptor)

Sphingosine 1-phosphate (S1P) is a lysosphingolipid associated with high-density lipoproteins (HDL) that contributes to their anti-atherogenic potential. We investigated whether a reduction in S1P plasma levels affects atherosclerosis in low-density lipoprotein receptor deficient (LDL-R-/-) mice.. LDL-R-/- mice on Western diet containing low (0.25% w/w) or high (1.25% w/w) cholesterol were treated for 16 weeks with SKI-II, a sphingosine kinase 1 inhibitor that significantly reduced plasma S1P levels. SKI-II treatment increased atherosclerotic lesions in the thoracic aorta in mice on high but not low cholesterol diet. This compound did not affect body weight, blood cell counts and plasma total and HDL cholesterol, but decreased triglycerides. In addition, mice on high cholesterol diet receiving SKI-II showed elevated levels of tumor necrosis factor-α and endothelial adhesion molecules (sICAM-1, sVCAM-1).. Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Atherosclerosis; Biomarkers; Cholesterol, Dietary; Cholesterol, HDL; Diet, Western; Disease Models, Animal; Enzyme Inhibitors; Female; Hypercholesterolemia; Intercellular Adhesion Molecule-1; Lysophospholipids; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Receptors, LDL; Risk Factors; Sphingosine; Thiazoles; Time Factors; Triglycerides; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Sphingosine 1-phosphate (S1P), a lysosphingolipid associated with high-density lipoprotein (HDL), contributes to the anti-atherogenic potential attributed to this lipoprotein. This study examined whether a reduction of S1P plasma levels affects atherosclerosis in a murine model of disease. LDL-R(-/-)mice on Western diet were given ABC294640, an inhibitor of sphingosine kinase (SphK) for 16 weeks. ABC294640 decreased plasma S1P by approximately 30%. However, ABC294640 failed to affect atherosclerotic lesion formation. Plasma triglycerides were reduced whereas total and HDL-cholesterol remained unchanged in course of ABC294640 treatment. ABC294640 increased plasma interleukin (IL)-12p70 and RANTES concentration as well as IL-12p70, RANTES and interferon (IFN)-γ production by peritoneal cells and this was paralleled by enhanced activity of peritoneal and spleen dendritic cells as evidenced by up-regulation of CD86 and MHC-II on CD11c(+) cells. As a consequence, increased T-cell activation was noted in ABC294640-treated mice as indicated by enhanced CD4(+) splenocyte proliferation, IFN-γ and IL-2 production, and CD69 expression. Concomitantly, however, ABC294640 treatment redistributed CD4(+) and CD8(+) cells from blood to lymphatic organs and reduced T-cell number within atherosclerotic lesions. In addition, plasma sVCAM-1, sICAM-1, and MCP-1 levels as well as in vivo leukocyte adhesion and CCL19-induced T-cell penetration into peritoneum were lower in ABC294640-treated animals. In vitro experiments demonstrated reduced VCAM-1 and ICAM-1 expression and lymphocyte adhesion to endothelial cells exposed to ABC294640. In conclusion, treatment with SphK inhibitor leads to both pro- and anti-atherogenic effects in LDL-R(-/-) mice. As a consequence, SphK inhibition fails to affect atherosclerosis despite significant S1P reduction in plasma.

Topics: Adamantane; Animals; Atherosclerosis; Cell Adhesion Molecules; Cell Differentiation; Cell Movement; Cell Proliferation; Cells, Cultured; Cytokines; Dendritic Cells; Disease Models, Animal; Disease Progression; Endothelium, Vascular; Enzyme Inhibitors; Humans; Inflammation Mediators; Mice; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Proprotein Convertases; Pyridines; Receptors, LDL; Serine Endopeptidases; T-Lymphocytes

The role of sphingosine-1-phosphate (S1P) and its receptors in the pathogenesis of atherosclerosis has not been investigated.. We hypothesized that the S1P receptor 3 (S1P(3)) plays a causal role in the pathogenesis of atherosclerosis.. We examined atherosclerotic lesion development in mice deficient for S1P(3) and apolipoprotein (Apo)E. Although S1P(3) deficiency did not affect lesion size after 25 or 45 weeks of normal chow diet, it resulted in a dramatic reduction of the monocyte/macrophage content in lesions of S1P(3)(-/-)/ApoE(-/-) double knockout mice. To search for putative defects in monocyte/macrophage recruitment, we examined macrophage-driven inflammation during thioglycollate-induced peritonitis. Elicited peritoneal macrophages were reduced in S1P(3)-deficient mice and expressed lower levels of tumor necrosis factor-α and monocyte chemoattractant protein-1. Bone marrow-derived S1P(3)-deficient macrophages produced less MCP-1 in response to lipopolysaccharide stimulation. In vitro, S1P was chemotactic for wild-type but not S1P(3)-deficient peritoneal macrophages. In vivo, S1P concentration increased rapidly in the peritoneal cavity after initiation of peritonitis. Treatment with the S1P analog FTY720 attenuated macrophage recruitment to the peritoneum. Studies in bone marrow chimeras showed that S1P(3) in both hematopoietic and nonhematopoietic cells contributed to monocyte/macrophage accumulation in atherosclerotic lesions. Finally, S1P(3) deficiency increased the smooth muscle cell content of atherosclerotic lesions and enhanced neointima formation after carotid ligation arguing for an antiproliferative/antimigratory role of S1P(3) in the arterial injury response.. Our data suggest that S1P(3) mediates the chemotactic effect of S1P in macrophages in vitro and in vivo and plays a causal role in atherosclerosis by promoting inflammatory monocyte/macrophage recruitment and altering smooth muscle cell behavior.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Cell Movement; Cell Proliferation; Disease Models, Animal; Fingolimod Hydrochloride; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Peritonitis; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Thioglycolates

The transformation of macrophages into foam cells is a critical event in the development of atherosclerosis. The most studied aspect of this process is the uptake of modified LDL through the scavenger receptors. Another salient aspect is the effect of modified LDL immune complexes on macrophages activation and foam cell formation. Macrophages internalize oxidized LDL immune complexes (oxLDL-IC) via the Fc-gamma receptor and transform into activated foam cells. In this study we examined the effect of oxLDL-IC on sphingosine kinase 1 (SK1), an enzyme implicated in mediating pro-survival and inflammatory responses through the generation of the signaling molecule sphingosine-1-phosphate (S1P). Intriguingly, oxLDL-IC, but not oxLDL alone, induced an immediate translocation and release of SK1 into the conditioned medium as evidenced by fluorescence confocal microscopy. Immunoblot analysis of cell lysates and conditioned medium revealed a decrease in intracellular SK1 protein levels accompanied by a concomitant increase in extracellular SK1 levels. Furthermore, measurement of S1P formation showed that the activity of cell-associated SK decreased in response to oxLDL-IC compared to oxLDL alone, whereas the activity of SK increased extracellularly. Blocking oxLDL-IC binding to Fc-gamma receptors resulted in decreased levels of extracellular S1P. The data also show that cell survival of human U937 cells exposed to oxLDL-IC increased compared to oxLDL alone. Exogenously added S1P further increased cell survival induced by oxLDL-IC. Taken together, these findings indicate that S1P may be generated extracellularly in response to modified LDL immune complexes and may therefore promote cell survival and prolong cytokine release by activated macrophages.

Topics: Antigen-Antibody Complex; Atherosclerosis; Cell Survival; Foam Cells; Humans; Inflammation; Lipoproteins, LDL; Macrophage Activation; Phosphotransferases (Alcohol Group Acceptor); Receptors, IgG; Signal Transduction; U937 Cells