Reviews

Sphingolipid Mediators in Cardiovascular Cell Biology and Pathology

Thierry Levade, Nathalie Augé, Robert Jan Veldman, Olivier Cuvillier, Anne Nègre-Salvayre, Robert Salvayre
https://doi.org/10.1161/hh2301.100350
Circulation Research. 2001;89:957-968
Originally published November 23, 2001

Jump to

Abstract

Sphingolipids have emerged as a new class of lipid mediators. In response to various extracellular stimuli, sphingolipid turnover can be stimulated in vascular cells and cardiac myocytes. Subsequent generation of sphingolipid molecules such as ceramide, sphingosine, and sphingosine-1-phosphate, is followed by regulation of ion fluxes and activation of various signaling pathways leading to smooth muscle cell proliferation, endothelial cell differentiation or apoptotic cell death, cell contraction, retraction, or migration. The importance of sphingolipids in cardiovascular signaling is illustrated by recent observations implicating them in physiological processes such as vasculogenesis as well as in frequent pathological conditions, including atherosclerosis and its complications.

Sphingolipids (SLs), which are found in many living organisms (from yeast, plants, to humans) and in virtually all cell types, comprise more than 300 species. At least in mammalian cells, they have been regarded mostly as structural elements of membranes for almost one century. It is only recently that the first evidence was provided in favor of a biomodulatory role of some SLs, in particular the sphingomyelin (SM) metabolites.1,2 A wealth of reports has now accumulated, on a wide variety of cell types of different animal species, supporting an unquestionable role of SLs in regulating numerous cell functions and possibly mediating the effects of extracellular stimuli.

We will review the actions of SLs on the different cardiovascular system cell types. The potential implications of SLs in physiological and pathological processes affecting cardiac and vascular cells will also be discussed. Because the particular role of glycosphingolipids, and notably lactosylceramide (LacCer), in vascular signaling has recently been reviewed,3 attention will be mainly paid here to the sphingophospholipids and the other SM-derived molecules. In addition, only the potential second-messenger functions of SLs in mammalian cells will be considered. Thus, the role of SL-metabolizing enzymes such as the secreted sphingomyelinase in the conversion of circulating lipoproteins to atherogenic particles will not be detailed (the reader is referred to recent reviews4,5).

Sphingolipid Structure and Metabolism

Understanding the possible cell regulatory functions of SLs needs a precise knowledge of how they are generated, degraded, or interconverted, and where they are located or metabolized. We will briefly review these biochemical aspects (see other references for details6–8).

Structure and Subcellular Distribution

SLs are defined by the presence of a long-chain sphingoid backbone, generally sphingosine (Figure 1). Acylation of the sphingoid base, ie, addition of a C16 to C24 fatty acid, on the amino group yields ceramide, which serves as a building block for most of the SLs. Different substitutions at the 1-hydroxyl position of ceramide define the various SL classes: addition of a phosphate or phosphocholine group results in the formation of sphingophospholipids (ceramide-1-phosphate and SM [ceramide-phosphocholine], respectively) whereas incorporation of carbohydrates leads to the complex group of glycosphingolipids. Lysosphingolipids represent SL variants consisting of N-deacylated derivatives. They include sphingosine-1-phosphate (S1P) and sphingosylphosphocholine (SPC), which are also sphingophospholipids (Figure 1).

Figure1

Figure 1. Structure and metabolism of signaling-involved sphingolipids. Details on the enzymes and their subcellular localization are provided in Table 1 according to the indicated reaction numbers. FA indicates fatty acid.

Because of their amphiphilic structure, most SLs are located in membrane bilayers. Most subcellular membranes contain SLs, although the plasma membrane and functionally related organelles are enriched in SLs8,9 (Figure 2). Within the plasma membrane, they are predominantly found in the outer leaflet. Importantly, the lateral distribution of SLs at the cell surface is not homogeneous. Rather, SLs are concentrated in microdomains, either rafts or caveolae, now believed to serve as signal-initiating platforms since a variety of proteins involved in signal transduction are located (or are translocated) there.10 As components of these structures, SM and glycosphingolipids could be implicated in initiating signaling events.11 Finally, SLs (in particular SM) are also found in each of the lipoprotein classes.9

Figure2

Figure 2. Main intracellular pathways for sphingolipid metabolism. The indicated numbers refer to the enzyme reactions given in Figure 1 and Table 1. DH-Sph indicates dihydrosphingosine; Sph, sphingosine; and GSL, glycosphingolipids.

Sphingolipid Turnover

The following section gives an overview of the main routes of the (glyco)sphingolipid metabolism, together with the involved enzymes and their subcellular localization (Figure 2 and Table 1), concentrating on the SLs that are believed to be involved in signal transduction.

View this table:
Table 1.

Sphingolipid-Metabolizing Enzymes Potentially Implicated in Signaling

De novo biosynthesis of ceramide takes place in the endoplasmic reticulum (ER) and starts with the formation by serine palmitoyl-transferase of 3-keto-sphinganine, which is then reduced to sphinganine (dihydrosphingosine) by 3-keto-sphinganine reductase.12 Ceramide synthase subsequently acylates sphinganine with an unbranched acyl chain, yielding dihydroceramide. Immediately, introduction of the C4–5 trans double bond by dihydroceramide desaturase occurs at the cytosolic face of the ER.13,14

Ceramide is primarily used for the synthesis of the phospholipid SM (Figure 2). In this reaction, a phosphocholine headgroup is transferred from phosphatidylcholine to ceramide.6,9 The SM synthase responsible for this reaction mainly resides in the cis and medial Golgi stacks,15,16 but contributions by the plasma membrane and a site in the endocytic recycling pathway have also been reported.17,18 The exact mechanism of ceramide transport from the ER to the Golgi and its translocation across the Golgi membrane (a prerequisite for the luminal event of SM biosynthesis) remain unknown.

Glucose and/or galactose can also be added to ceramide, yielding glucosylceramide (GlcCer) and galactosylceramide, respectively. Thereafter, GlcCer can be further glycosylated by the addition of galactose, resulting in the formation of LacCer, which in turn can give rise to more complex glycosphingolipids.7 These glycosylation steps are carried out by transferases restricted to the luminal face of the Golgi. An exception is the cytosol-oriented GlcCer synthase.19 After synthesis, SLs are transported to the plasma membrane, mostly by vesicular bulk flow.8

Ceramide can also be subjected to a phosphorylation/dephosphorylation cycle, which is mediated by a specific ceramide kinase20 and a ceramide-1-phosphate phosphatase,21 respectively.

Constitutive turnover of plasma membrane SLs mainly occurs after endocytosis (Figure 2). While a part of the internalized lipids is then recycled to the Golgi, or back to the plasma membrane, the remainder is degraded in the lysosomes through stepwise hydrolytic cleavage.22 Sequential removal of the terminal hydrophilic portions of the glycosphingolipids by a series of glycosidases is eased by the so-called SL activator proteins and eventually results in ceramide release. SM is cleaved in acidic compartments by the lysosomal sphingomyelinase (SMase),23 releasing phosphocholine and ceramide. After removal of the amide-linked fatty acid by a ceramidase,24 the remaining sphingosine presumably translocates across the lysosomal membrane.

Along with the well-characterized lysosomal pathways, nonlysosomal degradation also exists implicating membrane-bound hydrolases with neutral/alkaline optimum pH (Table 1). These ill-defined enzymes, which include SMases and ceramidases,25–30 may play a significant role in signal transduction (see Enzymes Involved in Sphingolipid Signaling). Moreover, no details are known concerning the subsequent trafficking of sphingosine from the plasma membrane and/or the lysosomes to the cytosolic site of the ER, where it can be reutilized for ceramide synthesis. Sphingosine can also be phosphorylated by a cytosolic sphingosine kinase to form S1P,31 which can be dephosphorylated by an S1P phosphatase32,33 or degraded by an ER-associated S1P lyase.34

Sphingolipids as Mediators: Generation and Mode of Action

Enzymes Involved in Sphingolipid Signaling

Despite that various SLs are now regarded as biomodulators, it is still unclear which enzymes are implicated in the generation of these signaling lipids. Since the same SL can be synthesized or degraded in distinct compartments by different enzyme entities (see Figure 2 and Table 1), a given SL may have different sources. Indeed, various pathways exhibiting different subcellular locations have been proposed for the generation of SLs.35 For instance, production of ceramide has most often been reported to arise from SM turnover through increased SMase activity but also from enhanced de novo synthesis. Different enzymes have been described to be activated upon cell stimulation and to be responsible for SM hydrolysis, implicating different sites such as the plasma membrane (inner leaflet, outer leaflet, and microdomain pools) or the acidic compartments. The nature of the signaling SMase is still intensely debated.35 The same applies for the production of S1P, the level of which is controlled by the concerted activities of sphingosine kinase, S1P phosphatase, and S1P lyase.36 These fundamental questions well illustrate the current debate on SL functions in cell signaling, obviously awaiting the availability of specific enzyme inhibitors, further characterization of the enzymes, and molecular tools.

Another important aspect for the production of SL mediators is the apparent tight regulation of SL-generating enzymes. For instance, the extracellular stimuli-responsive SMase activity is activated by lipids, such as arachidonic acid and ceramide itself, and serine proteases; on the other hand, neutral SMase stimulation can be negatively manipulated by protein kinase C (PKC) isoforms and glutathione levels.35

Sphingolipid Targets

Although few proteins have been reported to interact in vitro with some SLs, most of the direct molecular targets of SLs remain unknown. Because of the pleiotropic effects ascribed to ceramide or S1P, it was soon suspected that these SLs have different targets. The ceramide targets include kinases (a serine-threonine and proline-directed ceramide-activated protein kinase),37 members of the mitogen-activated protein kinases (MAPKs),38–40 classic and atypical PKC,41–43 a cytosolic ceramide-activated protein phosphatase,44 and transcription factors45,46 (Table 2). The activating role of ceramide on nuclear factor-κB (NF-κB) has, however, been challenged.47–49 The subcellular location of ceramide generation is likely to play an important role in dictating its downstream targets and thereby the biological response of the cell to this mediator, also accounting for the diversity of ceramide actions.

View this table:
Table 2.

Intracellular Sphingolipid Targets

With regard to S1P, which is relatively water soluble, its effects depend on its source (ie, extracellular versus intracellular).50 Support for this dual mode of action has been brought by microinjection of S1P, the use of sphingosine kinase inhibitors, inhibition of S1P receptors by pertussis toxin, or more recently overexpression of sphingosine kinase. Agonist-stimulated sphingosine kinase leads to activation of MAPK, calcium mobilization, and inhibition of apoptogenic proteins.36 When released from cells (eg, platelets51,52), extracellular S1P acts as a ligand for the endothelial differentiation gene (EDG) family of G protein–coupled receptors.53 EDG-1 was identified as an immediate-early gene product in endothelial cells54 and was suggested to play a role in angiogenesis. The S1P-sensitive EDG family now includes EDG-1, -3, -5, -6, and -8.55 Upon binding of S1P to EDG-1, downstream events include the Gi-mediated activation of mitogenic pathways such as Ras and MAPK.56 In addition, EDG-1–coupled Gi protein induces a Fyn-mediated tyrosine phosphorylation of the cytoskeletal docking protein Cas (Crk-associated substrate), suggesting a role for EDG-1 in cytoskeletal remodeling and motility of (endothelial) cells.57 EDG-3 and EDG-5 are both coupled to G12/13 and to Gq.58 These routes converge on the small GTPase Rho that in turn activates p125FAK (focal adhesion kinase) and cadherin, again implicating EDG receptors in endothelial cell migration and differentiation.36 Little is known concerning the downstream signaling mechanisms of EDG-6 and EDG-8. The eventual cellular response to exogenous S1P will depend on the types of EDG receptors expressed and the extent of crosstalk between the involved signaling pathways.59

Biological Effects of Sphingolipids in Cardiovascular Cells

Exogenous SLs are able to induce in vitro various biological effects depending on the cell type. Moreover, several nonsphingolipidic molecules such as oxidized lipoproteins, cytokines, and growth factors, which are crucial players in vascular wall development and vascular pathology, stimulate various signaling pathways involving SLs. We have reviewed the main actions of SLs on cardiac myocytes and cells of the vascular wall (Table 3) (see also online Tables 1 and 2 available in the data supplement at http://www.circresaha.org).

View this table:
Table 3.

Pathophysiological Conditions Resulting in the Generation of Sphingolipids in Cardiovascular Cells

Sphingolipids in Modulation of Cell Proliferation

Several observations underline the role of SLs in the regulation of cell growth responses (see reviews3,5). Intracellularly produced ceramide, S1P, SPC, and LacCer can stimulate DNA synthesis in endothelial and smooth muscle cells (SMCs).60–62 They also potentiated the mitogenesis induced by various growth factors including platelet-derived growth factor (PDGF). Addition of these SLs to the cells or treatment with bacterial SMase was accompanied by an increased activity of MAPK,62 a key factor in cell proliferation.

The SMC proliferation induced by mitogens such as PDGF, fibroblast growth factor (FGF), epidermal growth factor (EGF), or insulin-like growth factor (IGF) but not endothelin-1 or the inflammatory cytokines interleukin-1 or tumor necrosis factor (TNF) (in contrast to other observations63) has been linked to the production of sphingosine through stimulation of a ceramidase.64 In fact, a decrease in ceramide content via an increased activity of ceramidase, SM synthase, or GlcCer synthase often correlates with a proliferative response. Activation of sphingosine kinase and generation of S1P is also stimulated by PDGF.65 Our group and others have reported that SMC proliferation could be due to a direct mitogenic effect of mildly or extensively oxidized LDL.60–62 Indeed, oxidized LDL–induced proliferation appeared to be partly dependent on SL generation,5 in particular through a cascade from SM to S1P,66 resulting in MAPK activation.62

In contrast, treatment with TNF (which produced ceramide) or with exogenous ceramide led to an inhibition of cell growth (online Table 1). On endothelial cells, this effect was related to a decrease in the retinoblastoma protein content and increased p53 level.67 Recently, the role of ceramide in the inhibition of SMC proliferation has been evaluated in a model of hypertensive rats: whereas in vascular SMCs from hypertensive rats a mitogenic response to TNF was found that was associated with inhibition of ceramide generation and SMase mRNA expression, none of these events were observed in SMCs from control animals.68

Sphingolipids in Apoptotic Cell Death

Exogenously added short-chain ceramides, but also sphingosine and its N-methyl derivative, as well as intracellular SMase overexpression, can induce apoptosis of various vascular wall cell types, cardiomyocytes, and macrophages (online Table 1). The particular issue of ceramide as a proapoptotic signaling molecule has recently been challenged.69,70 This debate was mostly based on the use of short-chain ceramide analogues, which, because of their physicochemical properties, might not fully mimic the natural SL. However, a number of environmental stresses result in intracellular ceramide production that precedes hallmarks of apoptosis2 (online Table 1). Apoptosis of endothelial cells during septic shock, due to lipopolysaccharide, has also been linked to ceramide generation.71

The signaling pathways involved in SL-induced endothelial cell apoptosis may include inhibition of survival pathways such as the PKB/Akt and/or activation of the classical caspase cascade.72 As for oxidized LDL–induced apoptosis, the proapoptotic role of ceramide production in endothelial cells is still uncertain.72–74 Interestingly, endothelial cell apoptosis triggered by exogenous ceramide could be prevented by overexpression of a Bcl-2 family member,75 addition of vascular endothelial growth factor (VEGF76), or generation of S1P,63 two factors promoting survival in this cell type. Of note, as reported in other cell types,77 a ceramide/S1P biostat seems to operate in vascular cells that modulate cell death or survival depending on the fine regulation of key SL-metabolizing enzymes. Hence, S1P can protect endothelial cells from apoptosis induced by growth factor withdrawal or ceramide treatment,51,78,79 possibly through action on EDG-1.78

Sphingolipids in Cell Migration

S1P and possibly also SPC mediate endothelial cell chemotaxis, suggesting a role as proangiogenic factors (see Sphingolipids in Angiogenesis and Vasculogenesis).59,80,81 S1P-induced cell migration involves activation of a Gi-coupled receptor phospholipase C calcium signaling, leading to tyrosine phosphorylation of p125FAK.52,82 Activation by S1P of Rho, Rac, and Cas (which are also critical for cell migration responses) through EDG-1 and EDG-3 receptors57,78,80,83–85 has also been reported. EDG-1 expression has recently been shown to be required for PDGF-directed chemotaxis of human aortic SMCs.84 Because PDGF stimulates sphingosine kinase,65 a crosstalk between PDGF and EDG-1 signaling probably exists.

Sphingolipids and Cell Adhesion

Several agents seem to induce expression of adhesion molecules via SL generation. For example, N-octanoyl-sphingosine, bacterial SMase, or TNF-induced ceramide production elicits E-selectin–dependent adhesion of quiescent neutrophils to human endothelial cells.86 Other investigators, however, have found a dissociation between TNF and ceramide in induction of gene expression.49 Conversely, TNF can induce sphingosine kinase activation and S1P generation resulting in increased E-selectin and vascular cell adhesion molecule (VCAM)-1 expression via NF-κB and MAPK activation.87,88 Moreover, VEGF induction of intercellular adhesion molecule (ICAM)-1, VCAM-1, and E-selectin has also been associated with sphingosine kinase, NF-κB, and PKC activation.89 On the other hand, TNF-induced expression of ICAM-1 in endothelial cells has been linked to the production of LacCer90 but not ceramide,91 which could act through NADPH oxidase–mediated superoxide generation.

Sphingolipids and Ion Fluxes

Ten years ago, Ghosh et al92 discovered that sphingosine mediated rapid and profound release of calcium from intracellular stores and proposed that this effect might be mediated by S1P. Later, it was observed that both sphingosine and S1P were potent calcium-mobilizing agonists (online Table 2). More recently, several studies have indicated that S1P-induced calcium mobilization may also rely on EDG receptors.93,94 Ample evidence also indicates that SPC could mobilize calcium in SMCs or endothelial cells (online Table 2), although it is possible that it acts independently of EDG but through its high-affinity receptor.95 In myocytes, whereas S1P and SPC cause calcium mobilization by the ryanodine receptor,94,96 ceramide and sphingosine substantially inhibit the L-type calcium channel current.97–99 Similarly, sphingosine along with S1P (in a pertussis toxin–independent manner) leads to a pronounced inhibitory effect on inward sodium current in myocytes.99,100 In atrial myocytes, S1P activated Gi protein–regulated inwardly rectifying potassium channels93 whereas both S1P and SPC could activate muscarinic potassium current via a G-coupled receptor,101 such as EDG-3.102

Sphingolipids and Vascular Tone Regulation

Although a clear picture on the role of SLs in contractile functions within the blood vessel wall has not yet emerged, SLs modulate the vascular tone (online Table 1). Ceramide is capable of attenuating the contractile response to phenylephrine,103,104 an effect correlated with decreased intracellular calcium mobilization. Ceramide has also been suggested to account for the endothelium-independent, phospholipase A2–mediated vasodilation response to TNF.105 On the other hand, ceramide added to untreated arterial rings provoked a sustained vasoconstriction that was endothelium-independent.106 This contractile effect of ceramide on SMCs has been linked to a calcium-dependent activation of an Src kinase.107 Sphingosine could also impair endothelium-dependent relaxation.108 Finally, the sphingophospholipids S1P and SPC have been reported to induce contraction of mesenteric and intrarenal microvessels109 as well as coronary arterial strips.110 On precontracted coronary arteries, however, SPC induced an endothelium-dependent relaxation.111

These apparently divergent effects of SLs might be related to the ability of ceramide or lysosphingolipids to activate NO synthase (Table 2). Although S1P- or SPC-induced vasoconstriction was not affected by NO synthase inhibition109 and implicated Rho-kinase activation,110 the relaxing effect of SPC was associated with NO production and was inhibited by NO synthase blockers.111 In a different context, ceramide could attenuate the vasodilator response to bradykinin by decreasing NO in vascular endothelial cells.112 Further complexity in the vessel wall response is due to the fact that whereas SLs can induce NO production, NO can activate ceramide generation.113

Sphingolipids in Cardiovascular Biology and Pathology

Many observations indicate that SLs play an important role in normal and pathological situations, although their participation in the pathophysiology or progression of cardiovascular diseases is still speculative.

Sphingolipids in Angiogenesis and Vasculogenesis

Angiogenesis is the formation of new capillary networks from preexisting vasculature by sprouting and/or splitting of capillaries. This fundamental process is involved in physiological processes such as wound healing and uterine development. In addition, angiogenesis has been implicated in cancer, rheumatoid arthritis, diabetic retinopathy, and other pathological conditions.114 Angiogenesis involves proliferation, migration, adhesion, and differentiation of endothelial cells, which, in a later stage, are then lined up by SMCs. This intricate process is under the control of both pro- and antiangiogenic factors. In addition to VEGF and FGF, certain lipids, including gangliosides, prostaglandins, and lysophosphatidic acid, are also implicated. Recent data have underlined a major regulatory role for the lysosphingolipid S1P in angiogenesis.

The involvement of S1P in angiogenesis was first established in an in vitro model system.52,78,115 Not only is S1P able to increase proliferation and chemotaxis of endothelial cells, but it also stimulates tube formation of cells grown on collagen gels.80,115 The S1P released by platelets during clotting would account for most of the chemotactic activity of serum.81 Both EDG-1 and EDG-3 receptors were reported to regulate adherens junction assembly and formation of capillary-like networks.78 Furthermore, the observation that homozygous EDG-1–deficient mice die in utero as a result of massive embryonic hemorrhage demonstrated in vivo that S1P receptors are involved in blood vessel formation and maturation.116 Moreover, although S1P alone was unable to promote vessel formation in the avascular mouse cornea, it markedly enhanced the response to basic fibroblast growth factor (bFGF).81

In addition, studies on the zebrafish embryo have demonstrated that an S1P receptor plays a pivotal role in the regulation of cellular movements during heart morphogenesis.117 Indeed, the underlying cause of the myocardial cell migration defect found in the zebrafish mil phenotype is a mutation in a G protein–coupled receptor for S1P that alters its downstream signaling events including calcium mobilization and MAPK activation.

Sphingolipids in Atherosclerosis and Its Complications

Atherosclerotic lesions accumulate glycosphingolipids3 as well as ceramide, which could be generated by the secretory SMase, abundant in atheromata and able to aggregate LDL.4 Besides these observations, several lines of evidence involve SLs as potential mediators of the atherogenic process. First, some SLs may participate in the proliferation of vascular wall cells, favoring thickening and plaque stabilization. This is the case for S1P either released from activated platelets52,81 or produced intracellularly on oxidized LDL entry.66 Second, through an inflammatory response initiated by cytokines or oxidized LDL, lipids such as ceramide, LacCer, or S1P can upregulate adhesion molecule expression and induce adhesion and migration of monocytes, which are crucial events in initiation and progression of atherogenesis. In this respect, one of the antiatherogenic effects of HDL could be the inhibition of TNF-stimulated sphingosine kinase in endothelial cells.88 Third, SLs, eg, ceramide or sphingosine derivatives, may promote cell death (mostly by apoptosis) in the vascular wall, a process implicated in plaque erosion and associated thrombosis.118 SL-mediated apoptosis of cardiac myocytes could probably contribute to progressive heart failure and arrhythmia. Cardiac dysfunction in obesity has also been linked to increased myocardial levels of ceramide.119 Fourth, by modulating platelet activation and aggregation, glycolipids and sphingosine derivatives may favor thrombosis, as ceramide could do by affecting tissue factor91 or plasminogen activator inhibitor (PAI)-1120 release. A low plasma level of GlcCer has also been proposed as a risk factor for venous thrombosis.121 Finally, because of their effects on aortic or renal vasculature, SLs might be involved in hypertension.

Sphingolipids in Ischemia/Reperfusion

Ischemia and reperfusion lead to distinctive effects on tissues that are related to the metabolic changes induced by both hypoxia and reoxygenation. The reduction or arrest of blood supply in heart is followed by apoptosis, necrosis, and infarction.122 The reoxygenation process, although efficient in reducing ischemic damage, initiates additional cell injury including apoptosis,123 this effect being partly due to the generation of reactive oxygen species. The SM-ceramide signaling pathway is one of the pathways123 activated in response to myocardial ischemia/reperfusion.124 It is also involved in ischemic acute renal failure125 and postischemic neuronal cell death.126–128 Hypoxia/reoxygenation activates a neutral SMase and ceramide accumulation, which implicated the production of free radicals.129 This oxidative stress–sensitive ceramide production could activate in turn the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway, and antioxidants prevented both ceramide release and JNK activation. Further indication that ceramide may mediate some of the ischemic brain response was provided by the finding that ceramide increased expression of c-Jun and death-inducing ligands, ceramide induced both necrosis and apoptosis, and that the immunosuppressant FK506 inhibited the release of ceramide and apoptosis in a stroke model.126 Another recent study showed that the defect or inhibition of acid SMase activity led to reduced ischemic neuronal injury.128

Disagreeing with the above data, ceramide, either directly or as a downstream messenger of TNF, can induce tolerance to hypoxic/ischemic insults and partially reduces infarct size.130 These observations suggest that ceramide could in some cases exhibit a protective role against ischemic injury, as previously reported in heart or liver for sphingosine derivatives131,132 or glycolipids.133

Sphingolipids in Chemotherapy-Induced Cardiotoxicity and Irradiation-Induced Cytotoxicity

Some anticancer treatments are known to induce irreversible myocardial injury and/or endothelial cell death. This is the case for the anthracycline doxorubicin that causes cardiac toxicity134 and for ionizing radiation leading to endothelial cell apoptosis. Ceramide has been implicated in anthracycline-induced apoptosis of cardiac myocytes, not only because this SL was found to accumulate as a result of SMase action but also because its generation was blocked by l-carnitine, a compound known to prevent the drug-induced cardiac damage and which reduced apoptosis.135 Pretreatment of myocytes with fumonisin B1 did not protect from anthracycline-induced apoptosis, indicating that de novo ceramide formation is not required for apoptosis induction.136 Interestingly, SL involvement has also been reported in cardiomyocyte apoptosis triggered by TNF, another cytotoxic effector137; in this case, sphingosine was reported to act as mediator.

Microvascular damage seems to represent a critical factor in ionizing radiation injury of normal and tumor tissues, including the lung and central nervous sytem.138 Apoptosis of the endothelium participates in this acute radiation toxicity and implicates the rapid production of ceramide from membrane SM breakdown.139 Studies on the murine model of Niemann-Pick disease, which lacks acid SMase, have led to the conclusion that ceramide is required for radiation-induced apoptosis of the lung, spinal cord, or small intestine endothelium.140–142 Indeed, reduction of the apoptotic response was observed in the microvasculature of the above tissues, but not in thymus, of acid SMase–deficient mice. Moreover, ceramide-mediated apoptosis of endothelial cells in response to irradiation was antagonized by activation of PKC by phorbol esters or bFGF.141

Future Prospects: From Bench to Clinic?

Evidence has accumulated that SLs play crucial roles in modulating cell functions. Not only are SL-metabolizing enzymes or SL receptors present in yeast, nematodes, fishes, and mammals, suggesting an evolutionary conservation of these pathways, but also similar SL-mediated responses exist in human and yeast, insect, or amphibian cells. Although recent work has shown that some SLs appear to transduce signals leading to a series of events associated with the physiology and pathology of the cardiovascular system, further investigations are needed to clarify the role of SLs. Future studies should lead toward the characterization of the whole spectrum of SL-metabolizing enzymes, the structure-function relationships of SL (EDG) receptors, and the molecular targets of SLs. In particular, a clearer understanding of the role of SLs should be provided by studies on animals harboring disrupted genes of SL metabolism.

In addition, solving these issues is expected to result in the development of new strategies to prevent or limit cardiovascular diseases. Potential targets of therapeutic intervention are already identified, including pharmacological manipulation of SL metabolism and genetic approaches. Pharmacological inhibitors include various mycotoxins, which at micromolar concentrations are able to inhibit enzymes of ceramide synthesis143 or SMase,144 and various synthetic drugs such as PDMP and N-butyl-deoxynojirimycin, which block ceramide glucosylation. Although the fungal toxins cannot yet readily be used in humans because of their potent adverse effects, the chemical compounds have already been successfully used to lower the amount of trihexosylceramide in a murine model of Fabry disease, a lysosomal disorder mainly affecting endothelial cells.145 Future enzymatic studies will also probably result in the development of specific inhibitors of S1P kinase, phosphatase, and lyase, allowing manipulation of the level of this bioactive lipid. Another potential therapeutic strategy will be the use of S1P receptor antagonists (or agonists). Elucidation of the specific responses to S1P elicited by the different EDG receptors should yield compounds selective for a given receptor.

Of particular interest is the possibility of a local rather than systemic delivery of enzyme inhibitors or even SL analogues. For instance, balloon catheters coated with short-chain ceramide have recently been shown to reduce neointimal hyperplasia after stretch injury of rabbit carotid arteries,146 thus offering a novel pharmacotherapy to restenosis. A similar approach could be envisaged for antisense oligonucleotides directed against genes of SL-metabolizing enzymes. Thus, it is reasonably hoped that deciphering the signaling pathways triggered by SLs in cardiac and vascular cells will offer novel potential targets and promising approaches for therapeutic intervention in atherosclerosis and its complications, ischemic injury, neovascularization, wound healing, or other pathological states.

Acknowledgments

Financial support from INSERM and Université Paul Sabatier is gratefully acknowledged. The authors thank their collaborators for fruitful discussion.

Footnotes

  • Original received June 8, 2001; revision received October 8, 2001; accepted October 8, 2001.

References

  1. ↵
    Spiegel S, Merrill AH. Sphingolipid metabolism and cell growth regulation. FASEB J. 1996; 10: 1388–1397.
    OpenUrlAbstract
  2. ↵
    Hannun YA, Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000; 10: 73–80.
    OpenUrlCrossRefPubMed
  3. ↵
    Chatterjee S. Sphingolipids in atherosclerosis and vascular biology. Arterioscler Thromb Vasc Biol. 1998; 18: 1523–1533.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Tabas I. Secretory sphingomyelinase. Chem Phys Lipids. 1999; 102: 123–130.
    OpenUrlCrossRefPubMed
  5. ↵
    Augé N, Nègre-Salvayre A, Salvayre R, Levade T. Sphingomyelin metabolites in vascular cell signaling and atherogenesis. Prog Lipid Res. 2000; 39: 207–229.
    OpenUrlCrossRefPubMed
  6. ↵
    Merrill AH, Jones DD. An update of the enzymology and regulation of sphingomyelin metabolism. Biochim Biophys Acta. 1990; 1044: 1–12.
    OpenUrlPubMed
  7. ↵
    Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K. Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta. 2000; 1485: 63–99.
    OpenUrlPubMed
  8. ↵
    van Meer G, Holthuis JC. Sphingolipid transport in eukaryotic cells. Biochim Biophys Acta. 2000; 1486: 145–170.
    OpenUrlPubMed
  9. ↵
    Koval M, Pagano RE. Intracellular transport and metabolism of sphingomyelin. Biochim Biophys Acta. 1991; 1082: 113–125.
    OpenUrlPubMed
  10. ↵
    Brown DA, London E. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem. 2000; 275: 17221–17224.
    OpenUrlFREE Full Text
  11. ↵
    Prieschl EE, Baumruker T. Sphingolipids: second messengers, mediators and raft constituents in signaling. Immunol Today. 2000; 21: 555–560.
    OpenUrlCrossRefPubMed
  12. ↵
    Merrill AH, Wang E. Biosynthesis of long-chain (sphingoid) bases from serine by LM cells. J Biol Chem. 1986; 261: 3764–3769.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Mandon EC, Ehses I, Rother J, van Echten G, Sandhoff K. Subcellular localization and membrane topology of serine palmitoyltransferase, 3-dehydrosphinganine reductase, and sphinganine N-acyltransferase in mouse liver. J Biol Chem. 1992; 267: 11144–11148.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Michel C, van Echten-Deckert G, Rother J, Sandhoff K, Wang E, Merrill AH. Characterization of ceramide synthesis. J Biol Chem. 1997; 272: 22432–22437.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Futerman AH, Stieger B, Hubbard AL, Pagano RE. Sphingomyelin synthesis in rat liver occurs predominantly at the cis and medial cisternae of the Golgi apparatus. J Biol Chem. 1990; 265: 8650–8657.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Jeckel D, Karrenbauer A, Birk R, Schmidt RR, Wieland F. Sphingomyelin is synthesized in the cis Golgi. FEBS Lett. 1990; 261: 155–157.
    OpenUrlCrossRefPubMed
  17. ↵
    van Helvoort A, van’t Hof W, Ritsema T, Sandra A, van Meer G. Conversion of diacylglycerol to phosphatidylcholine on the basolateral surface of epithelial (Madin-Darby canine kidney) cells. J Biol Chem. 1994; 269: 1763–1769.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Miro Obradors MJ, Sillence D, Howitt S, Allan D. The subcellular sites of sphingomyelin synthesis in BHK cells. Biochim Biophys Acta. 1997; 1359: 1–12.
    OpenUrlPubMed
  19. ↵
    Coste H, Martel MB, Got R. Topology of glucosylceramide synthesis in Golgi membranes from porcine submaxillary glands. Biochim Biophys Acta. 1986; 858: 6–12.
    OpenUrlPubMed
  20. ↵
    Bajjalieh SM, Martin TF, Floor E. Synaptic vesicle ceramide kinase: a calcium-stimulated lipid kinase that co-purifies with brain synaptic vesicles. J Biol Chem. 1989; 264: 14354–14360.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Shinghal R, Scheller RH, Bajjalieh SM. Ceramide-1-phosphate phosphatase activity in brain. J Neurochem. 1993; 61: 2279–2285.
    OpenUrlCrossRefPubMed
  22. ↵
    Sandhoff K, Kolter T. Topology of glycosphingolipid degradation. Trends Cell Biol. 1996; 6: 98–103.
    OpenUrlCrossRefPubMed
  23. ↵
    Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ. Human acid sphingomyelinase: isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. J Biol Chem. 1991; 266: 8531–8539.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Koch J, Gärtner S, Li CM, Quintern LE, Bernardo K, Levran O, Schnabel D, Desnick RJ, Schuchman EH, Sandhoff K. Molecular cloning and characterization of a full-length cDNA encoding human acid ceramidase. J Biol Chem. 1996; 271: 33110–33115.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Tomiuk S, Hofmann K, Nix M, Zumbansen M, Stoffel W. Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Proc Natl Acad Sci U S A. 1998; 95: 3638–3643.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Chatterjee S, Han H, Rollins S, Cleveland T. Molecular cloning, characterization, and expression of a novel human neutral sphingomyelinase. J Biol Chem. 1999; 274: 37407–37412.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Hofmann K, Tomiuk S, Wolff G, Stoffel W. Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase. Proc Natl Acad Sci U S A. 2000; 97: 5895–5900.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Tani M, Okino N, Mori K, Tanigawa T, Izu H, Ito M. Molecular cloning of the full-length cDNA encoding mouse neutral ceramidase. J Biol Chem. 2000; 275: 11229–11234.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    El Bawab S, Roddy P, Qian T, Bielawska A, Lemasters JJ, Hannun YA. Molecular cloning and characterization of a human mitochondrial ceramidase. J Biol Chem. 2000; 275: 21508–21513.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Mao C, Xu R, Szulc ZM, Bielawska A, Galadari SH, Obeid LM. Cloning and characterization of a novel human alkaline ceramidase. J Biol Chem. 2001; 276: 26577–26588.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Kohama T, Olivera A, Edsall L, Nagiec MM, Dickson R, Spiegel S. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem. 1998; 273: 23722–23728.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    De Ceuster P, Mannaerts GP, Van Veldhoven PP. Identification and subcellular localization of sphinganine-phosphatases in rat liver. Biochem J. 1995; 311: 139–146.
  33. ↵
    Mandala SM, Thornton R, Galve-Roperh I, Poulton S, Peterson C, Olivera A, Bergstrom J, Kurtz MB, Spiegel S. Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1-phosphate and induces cell death. Proc Natl Acad Sci U S A. 2000; 97: 7859–7864.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    van Veldhoven PP, Gijsbers S, Mannaerts GP, Vermeesch JR, Brys V. Human sphingosine-1-phosphate lyase: cDNA cloning, functional expression studies and mapping to chromosome 10q22(1). Biochim Biophys Acta. 2000; 1487: 128–134.
    OpenUrlPubMed
  35. ↵
    Levade T, Jaffrézou JP. Signalling sphingomyelinases: which, where, how and why? Biochim Biophys Acta. 1999; 1438: 1–17.
    OpenUrlCrossRefPubMed
  36. ↵
    Pyne S, Pyne NJ. Sphingosine-1-phosphate signalling in mammalian cells. Biochem J. 2000; 349: 385–402.
    OpenUrlCrossRefPubMed
  37. ↵
    Mathias S, Dressler KA, Kolesnick RN. Characterization of a ceramide-activated protein kinase: stimulation by TNFα. Proc Natl Acad Sci U S A. 1991; 88: 10009–10013.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Raines MA, Kolesnick RN, Golde DW. Sphingomyelinase and ceramide activate mitogen-activated protein kinase in myeloid HL-60 cells. J Biol Chem. 1993; 268: 14572–14575.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Westwick JK, Bielawska AE, Dbaibo G, Hannun YA, Brenner DA. Ceramide activates the stress-activated protein kinases. J Biol Chem. 1995; 270: 22689–22692.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Verheij M, Bose R, Lin X, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LI, Kyriakis JM, Haimovitz-Friedman A, Fuks Z, Kolesnick RN. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature. 1996; 380: 75–79.
    OpenUrlCrossRefPubMed
  41. ↵
    Muller G, Ayoub M, Storz P, Rennecke J, Fabbro D, Pfizenmaier K. PKCζ is a molecular switch in signal transduction of TNFα, bifunctionally regulated by ceramide and arachidonic acid. EMBO J. 1995; 14: 1961–1969.
    OpenUrlPubMed
  42. ↵
    Lee JY, Hannun YA, Obeid LM. Ceramide inactivates cellular protein kinase Cα. J Biol Chem. 1996; 271: 13169–13174.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Huwiler A, Fabbro D, Pfeilschifter J. Selective ceramide binding to protein kinase C-α and -δ isoenzymes in renal mesangial cells. Biochemistry. 1998; 37: 14556–14562.
    OpenUrlCrossRefPubMed
  44. ↵
    Dobrowsky RT, Hannun YA. Ceramide stimulates a cytosolic protein phosphatase. J Biol Chem. 1992; 267: 5048–5051.
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Schütze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Krönke M. TNF activates NF-κB by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell. 1992; 71: 765–776.
    OpenUrlCrossRefPubMed
  46. ↵
    Boland MP, O’Neill LA. Ceramide activates NFκB by inducing the processing of p105. J Biol Chem. 1998; 273: 15494–15500.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    Dbaibo GS, Obeid LM, Hannun YA. TNFα signal transduction through ceramide. J Biol Chem. 1993; 268: 17762–17766.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Betts JC, Agranoff AB, Nabel GJ, Shayman JA. Dissociation of endogenous cellular ceramide from NF-κB activation. J Biol Chem. 1994; 269: 8455–8458.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    Slowik MR, De Luca LG, Min W, Pober JS. Ceramide is not a signal for TNF-induced gene expression but does cause programmed cell death in human vascular endothelial cells. Circ Res. 1996; 79: 736–747.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Hla T, Lee MJ, Ancellin N, Liu CH, Thangada S, Thompson BD, Kluk M. Sphingosine-1-phosphate: extracellular mediator or intracellular second messenger? Biochem Pharmacol. 1999; 58: 201–207.
    OpenUrlCrossRefPubMed
  51. ↵
    Hisano N, Yatomi Y, Satoh K, Akimoto S, Mitsumata M, Fujino MA, Ozaki Y. Induction and suppression of endothelial cell apoptosis by sphingolipids: a possible in vitro model for cell-cell interactions between platelets and endothelial cells. Blood. 1999; 93: 4293–4299.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    Yatomi Y, Ohmori T, Rile G, Kazama F, Okamoto H, Sano T, Satoh K, Kume S, Tigyi G, Igarashi Y, Ozaki Y. Sphingosine-1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells. Blood. 2000; 96: 3431–3438.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    Lee MJ, Van Brocklyn JR, Thangada S, Liu CH, Hand AR, Menzeleev R, Spiegel S, Hla T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science. 1998; 279: 1552–1555.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Hla T, Maciag T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein coupled receptors. J Biol Chem. 1990; 265: 9308–9313.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Spiegel S, Milstien S. Functions of a new family of sphingosine-1-phosphate receptors. Biochim Biophys Acta. 2000; 1484: 107–116.
    OpenUrlCrossRefPubMed
  56. ↵
    Okamoto H, Takuwa N, Gonda K, Okazaki H, Chang K, Yatomi Y, Shigematsu H, Takuwa Y. EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J Biol Chem. 1998; 273: 27104–27110.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    Ohmori T, Yatomi Y, Okamoto H, Miura Y, Rile G, Satoh K, Ozaki Y. Gi-mediated Cas tyrosine phosphorylation in vascular endothelial cells stimulated with sphingosine-1-phosphate: possible involvement in cell motility enhancement in cooperation with Rho-mediated pathways. J Biol Chem. 2001; 276: 5274–5280.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    Windh RT, Lee MJ, Hla T, An S, Barr AJ, Manning DR. Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H218/Edg-5 to the Gi, Gq, and G12 families of heterotrimeric G proteins. J Biol Chem. 1999; 274: 27351–27358.
    OpenUrlAbstract/FREE Full Text
  59. ↵
    Panetti TS, Nowlen J, Mosher DF. Sphingosine-1-phosphate and lysophosphatidic acid stimulate endothelial cell migration. Arterioscler Thromb Vasc Biol. 2000; 20: 1013–1019.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Augé N, Andrieu N, Nègre-Salvayre A, Thiers JC, Levade T, Salvayre R. The sphingomyelin-ceramide signaling pathway is involved in oxidized low density lipoprotein-induced cell proliferation. J Biol Chem. 1996; 271: 19251–19255.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    Chatterjee S, Bhunia AK, Snowden A, Han H. Oxidized low density lipoproteins stimulate galactosyltransferase activity, ras activation, p44 mitogen activated protein kinase and c-fos expression in aortic smooth muscle cells. Glycobiology. 1997; 7: 703–710.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    Augé N, Escargueil-Blanc I, Lajoie-Mazenc I, Suc I, Andrieu-Abadie N, Pieraggi MT, Chatelut M, Thiers JC, Jaffrézou JP, Laurent G, Levade T, Nègre-Salvayre A, Salvayre R. Potential role for ceramide in mitogen-activated protein kinase activation and proliferation of vascular smooth muscle cells induced by oxidized low density lipoprotein. J Biol Chem. 1998; 273: 12893–12900.
    OpenUrlAbstract/FREE Full Text
  63. ↵
    Xia P, Wang L, Gamble JR, Vadas MA. Activation of sphingosine kinase by TNFα inhibits apoptosis in human endothelial cells. J Biol Chem. 1999; 274: 34499–34505.
    OpenUrlAbstract/FREE Full Text
  64. ↵
    Coroneos E, Martinez M, McKenna S, Kester M. Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines. Implications for cellular proliferation and differentiation. J Biol Chem. 1995; 270: 23305–23309.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Olivera A, Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature. 1993; 365: 557–60.
    OpenUrlCrossRefPubMed
  66. ↵
    Augé N, Nikolova-Karakashian M, Carpentier S, Parthasarathy S, Nègre-Salvayre A, Salvayre R, Merrill AH, Levade T. Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low density lipoprotein in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase. J Biol Chem. 1999; 274: 21533–21538.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    Lopez-Marure R, Ventura JL, Sanchez L, Montano LF, Zentella A. Ceramide mimics TNFα in the induction of cell cycle arrest in endothelial cells. Eur J Biochem. 2000; 267: 4325–4333.
    OpenUrlPubMed
  68. ↵
    Johns DG, Webb RC, Charpie JR. Impaired ceramide signalling in spontaneously hypertensive rat vascular smooth muscle: a possible mechanism for augmented cell proliferation. J Hypertens. 2001; 19: 63–70.
    OpenUrlCrossRefPubMed
  69. ↵
    Hofmann K, Dixit VM. Ceramide in apoptosis: does it really matter? Trends Biochem Sci. 1998; 23: 374–377.
    OpenUrlCrossRefPubMed
  70. ↵
    Kolesnick R, Hannun YA. Ceramide and apoptosis. Trends Biochem Sci. 1999; 24: 224–225.
    OpenUrlCrossRefPubMed
  71. ↵
    Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S, Garzotto M, McLoughlin M, Gallily R, Edwards CK, Schuchman EH, Fuks Z, Kolesnick R. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med. 1997; 186: 1831–1841.
    OpenUrlAbstract/FREE Full Text
  72. ↵
    Harada-Shiba M, Kinoshita M, Kamido H, Shimokado K. Oxidized low density lipoprotein induces apoptosis in cultured human umbilical vein endothelial cells by common and unique mechanisms. J Biol Chem. 1998; 273: 9681–9687.
    OpenUrlAbstract/FREE Full Text
  73. ↵
    Escargueil-Blanc I, Andrieu-Abadie N, Caspar-Bauguil S, Brossmer R, Levade T, Nègre-Salvayre A, Salvayre R. Apoptosis and activation of the sphingomyelin-ceramide pathway induced by oxidized low density lipoproteins are not causally related in ECV-304 endothelial cells. J Biol Chem. 1998; 273: 27389–27395.
    OpenUrlAbstract/FREE Full Text
  74. ↵
    Deigner HP, Claus R, Bonaterra GA, Gehrke C, Bibak N, Blaess M, Cantz M, Metz J, Kinscherf R. Ceramide induces aSMase expression: implications for oxLDL-induced apoptosis. FASEB J. 2001; 15: 807–814.
    OpenUrlAbstract/FREE Full Text
  75. ↵
    Ackermann EJ, Taylor JK, Narayana R, Bennett CF. The role of antiapoptotic Bcl-2 family members in endothelial apoptosis elucidated with antisense oligonucleotides. J Biol Chem. 1999; 274: 11245–11252.
    OpenUrlAbstract/FREE Full Text
  76. ↵
    Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY, Hebbel RP. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res. 1999; 247: 495–504.
    OpenUrlCrossRefPubMed
  77. ↵
    Cuvillier O, Pirianov G, Kleuser B, Vanek PJ, Coso OA, Gutkind JS, Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996; 381: 800–803.
    OpenUrlCrossRefPubMed
  78. ↵
    Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha’afi RI, Hla T. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell. 1999; 99: 301–312.
    OpenUrlCrossRefPubMed
  79. ↵
    Kwon YG, Min JK, Kim KM, Lee DJ, Billiar TR, Kim YM. Sphingosine-1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. J Biol Chem. 2001; 276: 10627–10633.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    Wang F, Van Brocklyn JR, Hobson JP, Movafagh S, Zukowska-Grojec Z, Milstien S, Spiegel S. Sphingosine-1-phosphate stimulates cell migration through a Gi-coupled cell surface receptor. J Biol Chem. 1999; 274: 35343–35350.
    OpenUrlAbstract/FREE Full Text
  81. ↵
    English D, Welch Z, Kovala AT, Harvey K, Volpert OV, Brindley DN, Garcia JG. Sphingosine-1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. FASEB J. 2000; 14: 2255–2265.
    OpenUrlAbstract/FREE Full Text
  82. ↵
    Lee OH, Lee DJ, Kim YM, Kim YS, Kwon HJ, Kim KW, Kwon YG. Sphingosine-1-phosphate stimulates tyrosine phosphorylation of focal adhesion kinase and chemotactic motility of endothelial cells via the Gi protein-linked phospholipase C pathway. Biochem Biophys Res Commun. 2000; 268: 47–53.
    OpenUrlCrossRefPubMed
  83. ↵
    Okamoto H, Takuwa N, Yokomizo T, Sugimoto N, Sakurada S, Shigematsu H, Takuwa Y. Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3. Mol Cell Biol. 2000; 20: 9247–9261.
    OpenUrlAbstract/FREE Full Text
  84. ↵
    Hobson JP, Rosenfeldt HM, Barak LS, Olivera A, Poulton S, Caron MG, Milstien S, Spiegel S. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science. 2001; 291: 1800–1803.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Paik JH, Chae S, Lee MJ, Thangada S, Hla T. Sphingosine-1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of αvβ3- and β1-containing integrins. J Biol Chem. 2001; 276: 11830–11837.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    Modur V, Zimmerman GA, Prescott SM, McIntyre TM. Endothelial cell inflammatory responses to TNFα. J Biol Chem. 1996; 271: 13094–13102.
    OpenUrlAbstract/FREE Full Text
  87. ↵
    Xia P, Gamble JR, Rye KA, Wang L, Hii CS, Cockerill P, Khew-Goodall Y, Bert AG, Barter PJ, Vadas MA. TNFα induces adhesion molecule expression through the sphingosine kinase pathway. Proc Natl Acad Sci U S A. 1998; 95: 14196–14201.
    OpenUrlAbstract/FREE Full Text
  88. ↵
    Xia P, Vadas MA, Rye KA, Barter PJ, Gamble JR. High density lipoproteins interrupt the sphingosine kinase signaling pathway. J Biol Chem. 1999; 274: 33143–33147.
    OpenUrlAbstract/FREE Full Text
  89. ↵
    Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY. Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-κB. J Biol Chem. 2001; 276: 7614–7620.
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Bhunia AK, Arai T, Bulkley G, Chatterjee S. Lactosylceramide mediates TNFα-induced intercellular adhesion molecule-1 (ICAM-1) expression and the adhesion of neutrophil in human umbilical vein endothelial cells. J Biol Chem. 1998; 273: 34349–34357.
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Hirokawa M, Kitabayashi A, Kuroki J, Miura AB. Induction of tissue factor production but not the upregulation of adhesion molecule expression by ceramide in human vascular endothelial cells. Tohoku J Exp Med. 2000; 191: 167–176.
    OpenUrlCrossRefPubMed
  92. ↵
    Ghosh TK, Bian J, Gill DL. Intracellular calcium release mediated by sphingosine derivatives generated in cells. Science. 1990; 248: 1653–1656.
    OpenUrlAbstract/FREE Full Text
  93. ↵
    van Koppen CJ, Meyer zu Heringdorf D, Laser KT, Zhang C, Jakobs KH, Bünemann M, Pott L. Activation of a high affinity Gi protein-coupled plasma membrane receptor by sphingosine-1-phosphate. J Biol Chem. 1996; 271: 2082–2087.
    OpenUrlAbstract/FREE Full Text
  94. ↵
    Nakajima N, Cavalli AL, Biral D, Glembotski CC, McDonough PM, Ho PD, Betto R, Sandona D, Palade PT, Dettbarn CA, Klepper RE, Sabbadini RA. Expression and characterization of Edg-1 receptors in rat cardiomyocytes: calcium deregulation in response to sphingosine-1-phosphate. Eur J Biochem. 2000; 267: 5679–5686.
    OpenUrlPubMed
  95. ↵
    Xu Y, Zhu K, Hong G, Wu W, Baudhuin LM, Xiao Y, Damron DS. Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1. Nat Cell Biol. 2000; 2: 261–267.
    OpenUrlCrossRefPubMed
  96. ↵
    Betto R, Teresi A, Turcato F, Salviati G, Sabbadini RA, Krown K, Glembotski CC, Kindman LA, Dettbarn C, Pereon Y, Yasui K, Palade PT. Sphingosylphosphocholine modulates the ryanodine receptor/calcium-release channel of cardiac sarcoplasmic reticulum membranes. Biochem J. 1997; 322: 327–333.
  97. ↵
    McDonough PM, Yasui K, Betto R, Salviati G, Glembotski CC, Palade PT, Sabbadini RA. Control of cardiac Ca2+ levels: inhibitory actions of sphingosine on Ca2+ transients and L-type Ca2+ channel conductance. Circ Res. 1994; 75: 981–989.
    OpenUrlAbstract/FREE Full Text
  98. ↵
    Schreur KD, Liu S. Involvement of ceramide in inhibitory effect of IL-1β on L-type Ca2+ current in adult rat ventricular myocytes. Am J Physiol. 1997; 272: H2591–H2598.
    OpenUrlAbstract/FREE Full Text
  99. ↵
    Yasui K, Palade P. Sphingolipid actions on sodium and calcium currents of rat ventricular myocytes. Am J Physiol. 1996; 270: C645–C649.
    OpenUrlAbstract/FREE Full Text
  100. ↵
    MacDonell KL, Severson DL, Giles WR. Depression of excitability by sphingosine-1-phosphate in rat ventricular myocytes. Am J Physiol. 1998; 275: H2291–H2299.
    OpenUrlAbstract/FREE Full Text
  101. ↵
    Bunemann M, Liliom K, Brandts BK, Pott L, Tseng JL, Desiderio DM, Sun G, Miller D, Tigyi G. A novel membrane receptor with high affinity for lysosphingomyelin and sphingosine-1-phosphate in atrial myocytes. EMBO J. 1996; 15: 5527–5534.
    OpenUrlPubMed
  102. ↵
    Himmel HM, Meyer Zu Heringdorf D, Graf E, Dobrev D, Kortner A, Schuler S, Jakobs KH, Ravens U. Evidence for Edg-3 receptor-mediated activation of IK.ACh by sphingosine-1-phosphate in human atrial cardiomyocytes. Mol Pharmacol. 2000; 58: 449–454.
    OpenUrlAbstract/FREE Full Text
  103. ↵
    Johns DG, Osborn H, Webb RC. Ceramide: a novel cell signaling mechanism for vasodilation. Biochem Biophys Res Commun. 1997; 237: 95–97.
    OpenUrlCrossRefPubMed
  104. ↵
    Zheng T, Li W, Wang J, Altura BT, Altura BM. Effects of neutral sphingomyelinase on phenylephrine-induced vasoconstriction and Ca2+ mobilization in rat aortic smooth muscle. Eur J Pharmacol. 2000; 391: 127–135.
    OpenUrlCrossRefPubMed
  105. ↵
    Johns DG, Webb RC. TNFα-induced endothelium-independent vasodilation: a role for phospholipase A2-dependent ceramide signaling. Am J Physiol. 1998; 275: H1592–H1598.
    OpenUrlAbstract/FREE Full Text
  106. ↵
    Zheng T, Li W, Wang J, Altura BT, Altura BM. Sphingomyelinase and ceramide analogs induce contraction and rises in [Ca2+]i in canine cerebral vascular muscle. Am J Physiol Heart Circ Physiol. 2000; 278: H1421–H1428.
    OpenUrlAbstract/FREE Full Text
  107. ↵
    Ibitayo AI, Tsunoda Y, Nozu F, Owyang C, Bitar KN. Src kinase and PI3-kinase as a transduction pathway in ceramide-induced contraction of colonic smooth muscle. Am J Physiol. 1998; 275: G705–G711.
    OpenUrlAbstract/FREE Full Text
  108. ↵
    Murohara T, Kugiyama K, Ohgushi M, Sugiyama S, Ohta Y, Yasue H. Effects of sphingomyelinase and sphingosine on arterial vasomotor regulation. J Lipid Res. 1996; 37: 1601–1608.
    OpenUrlAbstract
  109. ↵
    Bischoff A, Czyborra P, Fetscher C, Meyer Zu Heringdorf D, Jakobs KH, Michel MC. Sphingosine-1-phosphate and sphingosylphosphorylcholine constrict renal and mesenteric microvessels in vitro. Br J Pharmacol. 2000; 130: 1871–1877.
    OpenUrlCrossRefPubMed
  110. ↵
    Todoroki-Ikeda N, Mizukami Y, Mogami K, Kusuda T, Yamamoto K, Miyake T, Sato M, Suzuki S, Yamagata H, Hokazono Y, Kobayashi S. Sphingosylphosphorylcholine induces Ca2+-sensitization of vascular smooth muscle contraction: possible involvement of rho-kinase. FEBS Lett. 2000; 482: 85–90.
    OpenUrlCrossRefPubMed
  111. ↵
    Mogami K, Mizukami Y, Todoroki-Ikeda N, Ohmura M, Yoshida K, Miwa S, Matsuzaki M, Matsuda M, Kobayashi S. Sphingosylphosphorylcholine induces cytosolic Ca2+ elevation in endothelial cells in situ and causes endothelium-dependent relaxation through nitric oxide production in bovine coronary artery. FEBS Lett. 1999; 457: 375–380.
    OpenUrlCrossRefPubMed
  112. ↵
    Zhang DX, Zou AP, Li PL. Ceramide reduces endothelium-dependent vasodilation by increasing superoxide production in small bovine coronary arteries. Circ Res. 2001; 88: 824–831.
    OpenUrlAbstract/FREE Full Text
  113. ↵
    Huwiler A, Pfeilschifter J, van den Bosch H. Nitric oxide donors induce stress signaling via ceramide formation in rat renal mesangial cells. J Biol Chem. 1999; 274: 7190–7195.
    OpenUrlAbstract/FREE Full Text
  114. ↵
    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000; 407: 249–257.
    OpenUrlCrossRefPubMed
  115. ↵
    Lee OH, Kim YM, Lee YM, Moon EJ, Lee DJ, Kim JH, Kim KW, Kwon YG. Sphingosine-1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 1999; 264: 743–750.
    OpenUrlCrossRefPubMed
  116. ↵
    Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ, Liu CH, Hla T, Spiegel S, Proia RL. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest. 2000; 106: 951–961.
    OpenUrlCrossRefPubMed
  117. ↵
    Kupperman E, An S, Osborne N, Waldron S, Stainier DY. A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development. Nature. 2000; 406: 192–195.
    OpenUrlCrossRefPubMed
  118. ↵
    Mallat Z, Tedgui A. Current perspective on the role of apoptosis in atherothrombotic disease. Circ Res. 2001; 88: 998–1003.
    OpenUrlAbstract/FREE Full Text
  119. ↵
    Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A. 2000; 97: 1784–1789.
    OpenUrlAbstract/FREE Full Text
  120. ↵
    Soeda S, Honda O, Shimeno H, Nagamatsu A. Sphingomyelinase and cell-permeable ceramide analogs increase the release of plasminogen activator inhibitor-1 from cultured endothelial cells. Thromb Res. 1995; 80: 509–518.
    OpenUrlCrossRefPubMed
  121. ↵
    Deguchi H, Fernandez JA, Pabinger I, Heit JA, Griffin JH. Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway. Blood. 2001; 97: 1907–1914.
    OpenUrlAbstract/FREE Full Text
  122. ↵
    Buja LM, Entman ML. Modes of myocardial cell injury and cell death in ischemic heart disease. Circulation. 1998; 98: 1355–1357.
    OpenUrlFREE Full Text
  123. ↵
    Gottlieb RA, Engler RL. Apoptosis in myocardial ischemia-reperfusion. Ann N Y Acad Sci. 1999; 874: 412–426.
    OpenUrlCrossRefPubMed
  124. ↵
    Bielawska AE, Shapiro JP, Jiang L, Melkonyan HS, Piot C, Wolfe CL, Tomei LD, Hannun YA, Umansky SR. Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion. Am J Pathol. 1997; 151: 1257–1263.
    OpenUrlPubMed
  125. ↵
    Zager RA, Iwata M, Conrad DS, Burkhart KM, Igarashi Y. Altered ceramide and sphingosine expression during the induction phase of ischemic acute renal failure. Kidney Int. 1997; 52: 60–70.
    OpenUrlPubMed
  126. ↵
    Herr I, Martin-Villalba A, Kurz E, Roncaioli P, Schenkel J, Cifone MG, Debatin KM. FK506 prevents stroke-induced generation of ceramide and apoptosis signaling. Brain Res. 1999; 826: 210–219.
    OpenUrlCrossRefPubMed
  127. ↵
    Nakane M, Kubota M, Nakagomi T, Tamura A, Hisaki H, Shimasaki H, Ueta N. Lethal forebrain ischemia stimulates sphingomyelin hydrolysis and ceramide generation in the gerbil hippocampus. Neurosci Lett. 2000; 296: 89–92.
    OpenUrlCrossRefPubMed
  128. ↵
    Yu ZF, Nikolova-Karakashian M, Zhou D, Cheng G, Schuchman EH, Mattson MP. Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis. J Mol Neurosci. 2000; 15: 85–97.
    OpenUrlCrossRefPubMed
  129. ↵
    Hernandez OM, Discher DJ, Bishopric NH, Webster KA. Rapid activation of neutral sphingomyelinase by hypoxia-reoxygenation of cardiac myocytes. Circ Res. 2000; 86: 198–204.
    OpenUrlAbstract/FREE Full Text
  130. ↵
    Chen Y, Ginis I, Hallenbeck JM. The protective effect of ceramide in immature rat brain hypoxia-ischemia involves up-regulation of bcl-2 and reduction of TUNEL-positive cells. J Cereb Blood Flow Metab. 2001; 21: 34–40.
    OpenUrlCrossRefPubMed
  131. ↵
    Thurman RG, Gao W, Connor HD, Mason RP, Lemasters JJ, Bozigian H, Adams LM. SPC-100270, a protein kinase C inhibitor, reduced hypoxic injury due to reperfusion following orthotopic liver transplantation in the rat. Transpl Int. 1994; 7: S167–S170.
  132. ↵
    Campbell B, Shin YK, Scalia R, Lefer AM. Beneficial effects of N,N,N-trimethylsphingosine following ischemia and reperfusion in the isolated perfused rat heart. Cardiovasc Res. 1998; 39: 393–400.
    OpenUrlAbstract/FREE Full Text
  133. ↵
    Kendler A, Dawson G. The role of glycosphingolipids in hypoxic cell injury. Adv Lipid Res. 1993; 25: 289–301.
    OpenUrlPubMed
  134. ↵
    Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996; 125: 47–58.
    OpenUrlCrossRefPubMed
  135. ↵
    Andrieu-Abadie N, Jaffrézou JP, Hatem S, Laurent G, Levade T, Mercadier JJ. l-Carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: role of inhibition of ceramide generation. FASEB J. 1999; 13: 1501–1510.
    OpenUrlAbstract/FREE Full Text
  136. ↵
    Sawyer DB, Fukazawa R, Arstall MA, Kelly RA. Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Circ Res. 1999; 84: 257–265.
    OpenUrlAbstract/FREE Full Text
  137. ↵
    Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJ, Sabbadini RA. TNFα-induced apoptosis in cardiac myocytes. J Clin Invest. 1996; 98: 2854–2865.
    OpenUrlCrossRefPubMed
  138. ↵
    Lin X, Fuks Z, Kolesnick R. Ceramide mediates radiation-induced death of endothelium. Crit Care Med. 2000; 28: N87–N93.
    OpenUrlCrossRefPubMed
  139. ↵
    Haimovitz-Friedman A, Kan C, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z, Kolesnick RN. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med. 1994; 180: 525–535.
    OpenUrlAbstract/FREE Full Text
  140. ↵
    Santana P, Pena LA, Haimovitz-Friedman A, Martin S, Green D, McLoughlin M, Cordon-Cardo C, Schuchman EH, Fuks Z, Kolesnick R. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell. 1996; 86: 189–199.
    OpenUrlCrossRefPubMed
  141. ↵
    Pena LA, Fuks Z, Kolesnick RN. Radiation-induced apoptosis of endothelial cells in the murine central nervous system: protection by fibroblast growth factor and sphingomyelinase deficiency. Cancer Res. 2000; 60: 321–327.
    OpenUrlAbstract/FREE Full Text
  142. ↵
    Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C, Kolesnick R. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001; 293: 293–297.
    OpenUrlAbstract/FREE Full Text
  143. ↵
    Merrill AH, Liotta DC, Riley RT. Fumonisins: fungal toxins that shed light on sphingolipid function. Trends Cell Biol. 1996; 6: 218–223.
    OpenUrlCrossRefPubMed
  144. ↵
    Tanaka M, Nara F, Suzuki-Konagai K, Hosoya T, Ogita T. Structural elucidation of scyphostatin, an inhibitor of membrane-bound neutral sphingomyelinase. J Am Chem Soc. 1997; 119: 7871–7872.
    OpenUrlCrossRef
  145. ↵
    Abe A, Gregory S, Lee L, Killen PD, Brady RO, Kulkarni A, Shayman JA. Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest. 2000; 105: 1563–1573.
    OpenUrlCrossRefPubMed
  146. ↵
    Charles R, Sandirasegarane L, Yun J, Bourbon N, Wilson R, Rothstein RP, Levison SW, Kester M. Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in carotid arteries. Circ Res. 2000; 87: 282–288.
    OpenUrlAbstract/FREE Full Text
  147. ↵
    Guo C, Zheng C, Martin-Padura I, Bian ZC, Guan JL. Differential stimulation of proline-rich tyrosine kinase 2 and mitogen-activated protein kinase by sphingosine-1-phosphate. Eur J Biochem. 1998; 257: 403–408.
    OpenUrlPubMed
  148. ↵
    Kimura T, Watanabe T, Sato K, Kon J, Tomura H, Tamama K, Kuwabara A, Kanda T, Kobayashi I, Ohta H, Ui M, Okajima F. Sphingosine-1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3. Biochem J. 2000; 348: 71–76.
  149. ↵
    Sekiguchi K, Yokoyama T, Kurabayashi M, Okajima F, Nagai R. Sphingosylphosphorylcholine induces a hypertrophic growth response through the mitogen-activated protein kinase signaling cascade in rat neonatal cardiac myocytes. Circ Res. 1999; 85: 1000–1008.
    OpenUrlAbstract/FREE Full Text
  150. ↵
    Kozawa O, Tanabe K, Ito H, Matsuno H, Niwa M, Kato K, Uematsu T. Sphingosine-1-phosphate regulates heat shock protein 27 induction by a p38 MAP kinase-dependent mechanism in aortic smooth muscle cells. Exp Cell Res. 1999; 250: 376–380.
    OpenUrlCrossRefPubMed
  151. ↵
    Yang L, Yatomi Y, Hisano N, Qi R, Asazuma N, Satoh K, Igarashi Y, Ozaki Y, Kume S. Activation of protein-tyrosine kinase Syk in human platelets stimulated with lysophosphatidic acid or sphingosine-1-phosphate. Biochem Biophys Res Commun. 1996; 229: 440–444.
    OpenUrlCrossRefPubMed
  152. ↵
    Johns DG, Jin JS, Wilde DW, Webb RC. Ceramide-induced vasorelaxation: an inhibitory action on protein kinase C. Gen Pharmacol. 1999; 33: 415–421.
    OpenUrlCrossRefPubMed
  153. ↵
    Igarashi J, Bernier SG, Michel T. Sphingosine-1-phosphate and activation of endothelial nitric-oxide synthase. J Biol Chem. 2001; 276: 12420–12426.
    OpenUrlAbstract/FREE Full Text
  154. ↵
    Morales-Ruiz M, Lee MJ, Zoellner S, Gratton JP, Scotland R, Shiojima I, Walsh K, Hla T, Sessa WC. Sphingosine-1-phosphate activates Akt, nitric oxide production and chemotaxis through a Gi-protein/phosphoinositide-3-kinase pathway in endothelial cells. J Biol Chem. 2001; 276: 19672–19677.
    OpenUrlAbstract/FREE Full Text
  155. ↵
    Miura Y, Yatomi Y, Rile G, Ohmori T, Satoh K, Ozaki Y. Rho-mediated phosphorylation of focal adhesion kinase and myosin light chain in human endothelial cells stimulated with sphingosine-1-phosphate. J Biochem. 2000; 127: 909–914.
    OpenUrlAbstract/FREE Full Text
  156. ↵
    Natarajan W, Jayaram HN, Scribner WN, Gracia JGN. Activation of endothelial cell phospholipase D by sphingosine and sphingosine-1-phosphate. Am J Respir Cell Mol Biol. 1994; 11: 221–229.
    OpenUrlPubMed
  157. ↵
    Masamune A, Igarashi Y, Hakomori S. Regulatory role of ceramide in interleukin (IL)-1-β-induced E-selectin expression in human umbilical vein endothelial cells. J Biol Chem. 1996; 271: 9368–9375.
    OpenUrlAbstract/FREE Full Text
  158. ↵
    Igarashi J, Thatte HS, Prabhakar P, Golan DE, Michel T. Calcium-independent activation of endothelial nitric oxide synthase by ceramide. Proc Natl Acad Sci U S A. 1999; 96: 12583–12588.
    OpenUrlAbstract/FREE Full Text
  159. ↵
    Arai T, Bhunia AK, Chatterjee S, Bulkley GB. Lactosylceramide stimulates human neutrophils to upregulate Mac-1, adhere to endothelium, and generate reactive oxygen metabolites in vitro. Circ Res. 1998; 82: 540–547.
    OpenUrlAbstract/FREE Full Text
  160. ↵
    Okamoto H, Yatomi Y, Ohmori T, Satoh K, Matsumoto Y, Ozaki Y. Sphingosine-1-phosphate stimulates G(i)- and Rho-mediated vascular endothelial cell spreading and migration. Thromb Res. 2000; 99: 259–265.
    OpenUrlCrossRefPubMed
  161. ↵
    Morrill GA, Gupta RK, Kostellow AB, Ma GY, Zhang A, Altura BT, Altura BM. Mg2+ modulates membrane sphingolipid and lipid second messenger levels in vascular smooth muscle cells. FEBS Lett. 1998; 440: 167–171.
    OpenUrlCrossRefPubMed
  162. ↵
    De Maria R, Boirivant M, Cifone MG, Roncaioli P, Hahne M, Tschopp J, Pallone F, Santoni A, Testi R. Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. J Clin Invest. 1996; 97: 316–322.
    OpenUrlCrossRefPubMed
  163. ↵
    Borchardt RA, Lee WT, Kalen A, Buckley RH, Peters C, Schiff S, Bell RM. Growth-dependent regulation of cellular ceramides in human T-cells. Biochim Biophys Acta. 1994; 1212: 327–336.
    OpenUrlPubMed
  164. ↵
    Boucher LM, Wiegmann K, Futterer A, Pfeffer K, Machleidt T, Schütze S, Mak TW, Krönke M. CD28 signals through acidic sphingomyelinase. J Exp Med. 1995; 181: 2059–2068.
    OpenUrlAbstract/FREE Full Text
  165. ↵
    Kinscherf R, Claus R, Wagner M, Gehrke C, Kamencic H, Hou D, Nauen O, Schmiedt W, Kovacs G, Pill J, Metz J, Deigner HP. Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent. FASEB J. 1998; 12: 461–467.
    OpenUrlAbstract/FREE Full Text
  166. ↵
    Yatomi Y, Yamamura S, Ruan F, Igarashi Y. Sphingosine-1-phosphate induces platelet activation through an extracellular action and shares a platelet surface receptor with lysophosphatidic acid. J Biol Chem. 1997; 272: 5291–5297.
    OpenUrlAbstract/FREE Full Text
View Abstract

This Issue

Jump to

Article Tools

Share this Article

  • Email
  • Sphingolipid Mediators in Cardiovascular Cell Biology and Pathology
    Thierry Levade, Nathalie Augé, Robert Jan Veldman, Olivier Cuvillier, Anne Nègre-Salvayre and Robert Salvayre
    Circulation Research. 2001;89:957-968, originally published November 23, 2001
    https://doi.org/10.1161/hh2301.100350
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects