sphingosine-1-phosphate and Atherosclerosis

Atherosclerosis-a systemic inflammatory disease-is the number one cause of mortality and morbidity worldwide. As such, the prevention of disease progression is of global interest in order to reduce annual deaths at a significant scale. Atherosclerosis is characterized by plaque formation in the arteries, resulting in vascular events such as ischemic stroke or myocardial infarction. A better understanding of the underlying pathophysiological processes at the cellular and molecular level is indispensable to identify novel therapeutic targets that may alleviate disease initiation or progression. Sphingolipids-a lipid class named after the chimeric creature sphinx-are considered to play a critical and, metaphorically, equally chimeric regulatory role in atherogenesis. Previous studies identified six common sphingolipids, namely dihydroceramide (DhCer), ceramide (Cer), sphingosine-1-phosphate (S1P), sphingomyelin (SM), lactosylceramide (LacCer), and glucosylceramide (GluCer) in carotid plaques, and demonstrated their potential as inducers of plaque inflammation. In this review, we point out their specific roles in atherosclerosis by focusing on different cell types, carrier molecules, enzymes, and receptors involved in atherogenesis. Whereas we assume mainly atheroprotective effects for GluCer and LacCer, the sphingolipids DhCer, Cer, SM and S1P mediate chimeric functions. Initial studies demonstrate the successful use of interventions in the sphingolipid pathway to prevent atherosclerosis. However, as atherosclerosis is a multifactorial disease with a variety of underlying cellular processes, it is imperative for future research to emphasize the circumstances in which sphingolipids exert protective or progressive functions and to evaluate their therapeutic benefits in a spatiotemporal manner.

Topics: Antigens, CD; Atherosclerosis; Ceramides; Chimera; Glucosylceramides; Humans; Lactosylceramides; Lysophospholipids; Plaque, Atherosclerotic; Sphingolipids; Sphingomyelins; Sphingosine

Atherosclerosis is characterized by focal accumulations of lipid within the arterial wall, thought to arise from effects of hemodynamic wall shear stress (WSS) on endothelial permeability. Identifying pathways that mediate the effects of shear on permeability could therefore provide new therapeutic opportunities. Here, we consider whether the sphingosine-1-phosphate (S1P) pathway could constitute such a route. We review effects of S1P in endothelial barrier function, the influence of WSS on S1P production and signaling, the results of trials investigating S1P in experimental atherosclerosis in mice, and associations between S1P levels and cardiovascular disease in humans. Although it seems clear that S1P reduces endothelial permeability and responds to WSS, the evidence that it influences atherosclerosis is equivocal. The effects of specifically pro- and anti-atherosclerotic WSS profiles on the S1P pathway require investigation, as do influences of S1P on the vesicular pathways likely to dominate low-density lipoprotein transport across endothelium.

Topics: Animals; Atherosclerosis; Endothelium; Hemodynamics; Lysophospholipids; Mice; Permeability; Sphingosine

Coronary artery disease (CAD) is a common cause of morbidity and mortality worldwide. Atherosclerotic plaques, as a hallmark of CAD, cause chronic narrowing of coronary arteries over time and could also result in acute myocardial infarction (AMI). The standard treatments for ameliorating AMI are reperfusion strategies, which paradoxically result in ischemic reperfusion (I/R) injury. Sphingosine 1 phosphate (S1P), as a potent lysophospholipid, plays an important role in various organs, including immune and cardiovascular systems. In addition, high-density lipoprotein, as a negative predictor of atherosclerosis and CAD, is a major carrier of S1P in blood circulation. S1P mediates its effects through binding to specific G protein-coupled receptors, and its signaling contributes to a variety of responses, including cardiac inflammation, dysfunction, and I/R injury protection. In this review, we will focus on the role of S1P in CAD and I/R injury as a potential therapeutic target.

Topics: Atherosclerosis; Coronary Artery Disease; Humans; Lipoproteins, HDL; Lysophospholipids; Myocardial Infarction; Protein Binding; Receptors, G-Protein-Coupled; Reperfusion Injury; Sphingosine

Sphingosine 1-phosphate (S1P) is a potent lipid mediator that works on five kinds of S1P receptors located on the cell membrane. In the circulation, S1P is distributed to HDL, followed by albumin. Since S1P and HDL share several bioactivities, S1P is believed to be responsible for the pleiotropic effects of HDL. Plasma S1P levels are reportedly lower in subjects with coronary artery disease, suggesting that S1P might be deeply involved in the pathogenesis of atherosclerosis. In basic experiments, however, S1P appears to possess both pro-atherosclerotic and anti-atherosclerotic properties; for example, S1P possesses anti-apoptosis, anti-inflammation, and vaso-relaxation properties and maintains the barrier function of endothelial cells, while S1P also promotes the egress and activation of lymphocytes and exhibits pro-thrombotic properties. Recently, the mechanism for the biased distribution of S1P on HDL has been elucidated; apolipoprotein M (apoM) carries S1P on HDL. ApoM is also a modulator of S1P, and the metabolism of apoM-containing lipoproteins largely affects the plasma S1P level. Moreover, apoM modulates the biological properties of S1P. S1P bound to albumin exerts both beneficial and harmful effects in the pathogenesis of atherosclerosis, while S1P bound to apoM strengthens anti-atherosclerotic properties and might weaken the pro-atherosclerotic properties of S1P. Although the detailed mechanisms remain to be elucidated, apoM and S1P might be novel targets for the alleviation of atherosclerotic diseases in the future.

Topics: Animals; Apolipoproteins M; Apoptosis; Atherosclerosis; Cell Line; Coronary Artery Disease; Homeostasis; Humans; Inflammation; Lipoproteins, HDL; Lymphocyte Activation; Lysophospholipids; Receptors, LDL; Sphingosine; Thrombosis; Vasodilation

Previous studies showed that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely related to risk of cardiovascular diseases. However, in the last few decades it became obvious that beyond its plasma level, HDL structure and function have a critical role in its anti-atherogenic efficacy. Apolipoprotein M (ApoM) is an HDL-associated plasma protein affecting HDL metabolism and exhibits various anti-atherosclerotic functions, such as protection against oxidation and regulation of cholesterol efflux. Sphingosine 1-phosphate (S1P) is a potent sphingolipid mediator that regulates numerous cellular responses including cell differentiation and migration, apoptosis and vascular inflammation. The majority of S1P is associated to ApoM containing HDL particles. Therefore, ApoM and S1P content of HDL have an impact on the atherosclerotic process. Moreover, HDL-ApoM and S1P content can be altered in several pathologic conditions such as coronary artery disease. This review covers the currently available data on the contribution of ApoM and S1P to HDL function in health and cardiovascular diseases. Orv Hetil. 2018; 159(5): 168-175.

Topics: Apolipoproteins M; Atherosclerosis; Cholesterol, HDL; Humans; Lipid Metabolism; Lipoproteins, HDL; Lysophospholipids; Sphingosine

Aging is defined as the progressive deterioration of physiological function with age. Incidence of many pathologies increases with age, including neurological and cardiovascular diseases and cancer. Aging tissues become less adaptable and renewable, and cells undergo senescence, a process by which they "irreversibly" stop dividing. Senescence has been shown to serve as a tumor suppression mechanism with clear desirable effects. However, senescence also has deleterious consequences, especially for cardiovascular, metabolic, and immune systems. Sphingolipids are a major class of lipids that regulate cell biology, owing to their structural and bioactive properties and diversity. Their involvement in the regulation of aging and senescence has been demonstrated and studied in multiple organisms and cell types, especially that of ceramide and sphingosine-1-phosphate; ceramide induces cellular senescence and sphingosine-1-phosphate delays it. These discoveries could be very useful in the future to understand aging mechanisms and improve therapeutic interventions.

Topics: Aging; Alzheimer Disease; Animals; Atherosclerosis; Biomarkers; Cellular Senescence; Ceramides; Diabetes Mellitus, Type 2; Humans; Immune System; Lysophospholipids; Metabolic Networks and Pathways; Models, Biological; Neoplasms; Sphingolipids; Sphingosine

Cardiovascular diseases (CVD) remain the leading cause of death in industrialized countries. One of the most significant risk factors for atherosclerosis is hypercholesterolemia. Its diagnostics is based on routine lipid profile analysis, including the determination of total cholesterol, low and high density lipoprotein cholesterol, and triglycerides. However in recent years, much attention has been paid to the crosstalk between the metabolic pathways of the cholesterol and sphingolipids biosynthesis. Sphingolipids are a group of lipids, containing a molecule of aliphatic alcohol sphingosine. These include sphingomyelins, cerebrosides, gangliosides and ceramides, sphingosines, and sphingosine-1-phosphate (S-1-P). It has been found that catabolism of sphingolipids is associated with catabolism of cholesterol. However, the exact mechanism of this interaction is still unknown. Particular attention as CVD inducer attracts ceramide (Cer). Lipoprotein aggregates isolated from atherosclerotic pluques are enriched with Cer. The level of Cer and sphingosine increases after ischemia reperfusion of the heart, in the infarction zone and in the blood, and also in hypertension. S-1-P exhibits pronounced cardioprotective properties. Its content sharply decreases with ischemia and myocardial infarction. S-1-P presents predominantly in HDL, and influences their multiple functions. Increased levels of Cer and sphingosine and decreased levels of S-1-P formed in the course of coronary heart disease can be an important factor in the development of atherosclerosis. It is proposed to use determination of sphingolipids in blood plasma as markers for early diagnosis of cardiac ischemia and for hypertension in humans. There are intensive studies aimed at correction of metabolism S-1-P. The most successful drugs are those that use S-1-P receptors as a targets, since all of its actions are receptor-mediated.. Serdechno-sosudistye zabolevaniia (SSZ) ostaiutsia osnovnoĭ prichinoĭ smerti v promyshlenno razvitykh stranakh. Odnim iz naibolee znachimykh faktorov riska razvitiia ateroskleroza iavliaetsia giperkholesterinemiia, pri diagnostike kotoroĭ osnovnoe vnimanie udeliaetsia reguliarnomu analizu lipidnogo profilia, vkliuchaia opredelenie obshchego kholesterina, kholesterina lipoproteinov nizkoĭ i vysokoĭ plotnosti i triglitseridov. Odnako v poslednie gody bol'shoe vnimanie udelialos' peresecheniiu metabolicheskikh puteĭ biosinteza kholesterina i sfingolipidov. Sfingolipidy – gruppa lipidov, kotorye vkliuchaiut molekulu alifaticheskogo spirta sfingozina. K nim otnosiatsia sfingomieliny, tserebrozidy, gangliozidy, tseramidy, sfingoziny i sfingozin-1-fosfat. Ustanovleno, chto katabolizm sfingolipidov sviazan s katabolizmom kholesterina. Odnako tochnyĭ mekhanizm étogo vzaimodeĭstviia do sikh por ne izvesten. Osoboe vnimanie v kachestve induktora SSZ privlekaet tseramid. Ustanovleno, chto agregirovannye lipoproteiny, izolirovannye iz ateroskleroticheskikh zon, obogashcheny tseramidami. Uroven' tseramida i sfingozina povyshaetsia pri ishemii/reperfuzii serdtsa, v zone infarkta i v krovi, a takzhe pri gipertonicheskoĭ bolezni. S-1-F obladaet iarko vyrazhennymi kardioprotektivnymi svoĭstvami. Ego kolichestvo rezko umen'shaetsia pri ishemii i infarkte miokarda. S-1-F preimushchestvenno soderzhitsia v strukture lipoproteinov vysokoĭ plotnosti (LPVP), chto vliiaet na ikh mnozhestvennye funktsii. Uvelichenie tseramida i sfingozina i snizhenie urovnia S-1-F v khode progressirovaniia koronarnoĭ bolezni serdtsa mozhet byt' vazhnym faktorom v razvitii ateroskleroza. Predlagaetsia ispol'zovat' opredelenie urovnia sfingolipidov v plazme krovi v kachestve markerov dlia ranneĭ diagnostiki ishemii serdtsa i pri gipertonii u liudeĭ. V poslednee vremia intensivno vedutsia raboty po sozdaniiu preparatov, sposobnykh korrektirovat' metabolizm S-1-F. Naibolee udachnymi iavliaiutsia preparaty, kotorye v kachestve misheni ispol'zuiut retseptory S-1-F, cherez kotorye realizuiutsia vse ego éffekty. V kachestve osnovnogo metoda testirovaniia étikh lipidov predlagaetsia ispol'zovanie khromato-mass-spektrometrii.

Topics: Atherosclerosis; Cardiovascular Diseases; Ceramides; Cholesterol, HDL; Humans; Hypercholesterolemia; Lysophospholipids; Sphingolipids; Sphingomyelins; Sphingosine; Triglycerides

The glycocalyx covers the human mammalian cells and plays important roles in stroke, inflammation and atherosclerosis. It has also been shown to be involved in endothelial mechanotransduction of shear stress. Shear stress induces the remodelling of the major component of the glycocalyx including glypican-1, a cell membrane heparan sulphate proteoglycan. Other factors, such as sphingosine-1-phosphate (S1P), protect the glycocalyx against syndecan-1 ectodomain shedding and induce the synthesis of heparan sulphate. In this study, we reviewed the role of shear stress and S1P in glycocalyx remodelling and revealed that the glycocalyx is a critical signalling platform, integrating the extracellular haemodynamic forces and chemical signalling, such as S1P, for determining the fate of endothelial cells and vascular diseases. This review integrated our current understanding of the structure and function of the glycocalyx and provided new insight into the role of the glycocalyx that might be helpful for investigating the underlying biological mechanisms in certain human diseases, such as atherosclerosis.

Topics: Animals; Atherosclerosis; Cell Membrane; Cytokines; Endothelial Cells; Gene Expression Regulation; Glycocalyx; Glypicans; Hemodynamics; Humans; Lysophospholipids; Mechanotransduction, Cellular; Sphingosine; Stress, Mechanical; Syndecans

Numerous epidemiologic studies revealed that high-density lipoprotein (HDL) is an important risk factor for coronary heart disease. There are several well-documented HDL functions such as reversed cholesterol transport, inhibition of inflammation, or inhibition of platelet activation that may account for the atheroprotective effects of this lipoprotein. Mechanistically, these functions are carried out by a direct interaction of HDL particle or its components with receptors localized on the cell surface followed by generation of intracellular signals. Several HDL-associated receptor ligands such as apolipoprotein A-I (apoA-I) or sphingosine-1-phosphate (S1P) have been identified in addition to HDL holoparticles, which interact with surface receptors such as ATP-binding cassette transporter A1 (ABCA1); S1P receptor types 1, 2, and 3 (S1P1, S1P2, and S1P3); or scavenger receptor type I (SR-BI) and activate intracellular signaling cascades encompassing kinases, phospholipases, trimeric and small G-proteins, and cytoskeletal proteins such as actin or junctional protein such as connexin43. In addition, depletion of plasma cell cholesterol mediated by ABCA1, ATP-binding cassette transporter G1 (ABCG1), or SR-BI was demonstrated to indirectly inhibit signaling over proinflammatory or proliferation-stimulating receptors such as Toll-like or growth factor receptors. The present review summarizes the current knowledge regarding the HDL-induced signal transduction and its relevance to athero- and cardioprotective effects as well as other physiological effects exerted by HDL.

Topics: Adenosine Triphosphatases; Animals; Apolipoprotein A-I; Arteries; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Humans; Ligands; Lipoproteins, HDL; Lysophospholipids; Receptors, Lipoprotein; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Scavenger Receptors, Class B; Signal Transduction; Sphingosine

The bioactive lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P), have potent effects on blood and vascular cells. This review focuses their potential contributions to the development of atherosclerosis, acute complications such as acute myocardial infarction, and chronic ischemic cardiac damage.. Exciting recent developments have provided insight into the molecular underpinnings of LPA and S1P receptor signaling. New lines of evidence suggest roles for these pathways in the development of atherosclerosis. In experimental animal models, the production, signaling, and metabolism of LPA may be influenced by environmental factors in the diet that synergize to promote the progression of atherosclerotic vascular disease. This is supported by observations of human polymorphisms in the lysophospholipid-metabolizing enzyme PPAP2B, which are associated with risk of coronary artery disease and myocardial infarction. S1P signaling protects from myocardial damage that follows acute and chronic ischemia, both by direct effects on cardiomyocytes and through stem cell recruitment to ischemic tissue.. This review will suggest novel strategies to prevent the complications of coronary artery disease by targeting LPA production and signaling. Additionally, ways in which S1P signaling pathways may be harnessed to attenuate ischemia-induced cardiac dysfunction will be explored.

Topics: Animals; Atherosclerosis; Coronary Artery Disease; Humans; Lysophospholipids; Myocardial Ischemia; Signal Transduction; Sphingosine

Atherosclerosis is one of the leading causes of death in Japan. With accumulating data from animal experiments, it has become recognized that atherosclerosis involves a chronic inflammatory process of the arterial wall with a dyslipidemic background. However, clinical applications utilizing this knowledge remain scarce. In spite of optimal interventional and pharmacologic therapies, the risk of recurrent ischemia remains high and novel therapies to prevent atherogenesis or detect atherosclerosis in the early stage are needed. One of the potential molecular inflammatory targets that may be clinically relevant is natural killer T cells (NKT cells). Sphingosine-1-phosphate(S1P), one of the biologically active sphingolipids, increases TNF-α production in NKT cells and induces the migration of NKT cells, suggesting that S1P can regulate inflammatory processes in atherogenesis. Patients with high plasma S1P levels exhibit high levels of plasma TNF-α, plasma antigen levels of plasminogen activator inhibitor (PAI) -1, the major physiologic inhibitors of fibrinolysis, and a reduced endothelial function as assessed by the flow-mediated dilation of brachial arteries (FMD). Also, recent advances in research on circulating microRNA derived from endothelial cells are discussed as potential biomarkers of atherosclerosis. Specific efforts that promote translational science are encouraged to improve the outcome and prognosis of patients with atherosclerosis.

Topics: Animals; Atherosclerosis; Biomarkers; Body Mass Index; Humans; Lysophospholipids; MicroRNAs; Natural Killer T-Cells; Plasminogen Activator Inhibitor 1; Receptors, Lysosphingolipid; Sphingosine; Tumor Necrosis Factor-alpha

The structurally simple glycero- and sphingo-phospholipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate, serve as important receptor-active mediators that influence blood and vascular cell function and are positioned to influence the events that contribute to the progression and complications of atherosclerosis. Growing evidence from preclinical animal models has implicated LPA, LPA receptors, and key enzymes involved in LPA metabolism in pathophysiologic events that may underlie atherosclerotic vascular disease. These observations are supported by genetic analysis in humans implicating a lipid phosphate phosphatase as a novel risk factor for coronary artery disease. In this review, we summarize current understanding of LPA production, metabolism, and signaling as may be relevant for atherosclerotic and other vascular disease.

Topics: Adipose Tissue; Animals; Apolipoproteins E; Atherosclerosis; Coronary Artery Disease; Genetic Predisposition to Disease; Humans; Lysophospholipids; Mice; Mice, Knockout; Phosphatidate Phosphatase; Phosphoric Diester Hydrolases; Plaque, Atherosclerotic; Risk; Sphingosine

Chemokines are a diverse group of molecules with important implications for the development of solid tissues and normal function of the immune system. However, change of the conditions for such a complex system can have important and dangerous consequences leading to diseases. The specific implications of the various chemokines in diseases have been elucidated in the last few years, prompting hope of manipulating this system for therapy or prevention of diseases. On the other hand, inflammatory lipids are biologically active molecules with crucial impacts on the function of various cell types, including immune cells in health and disease. Here, we describe how these lipids affect the chemokine system and how they interact with chemokines to shape chronic inflammation in the case of atherosclerosis.

Topics: Animals; Atherosclerosis; Chemokines; Dendritic Cells; Humans; Linoleic Acids; Linoleic Acids, Conjugated; Lipids; Lipoproteins, LDL; Lysophospholipids; Receptors, Chemokine; Sphingosine

Numerous epidemiological studies documented an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and the extent of atherosclerotic disease. However, clinical interventions targeting HDL cholesterol failed to show clinical benefits with respect to cardiovascular risk reduction, suggesting that HDL components distinct from cholesterol may account for anti-atherogenic effects attributed to this lipoprotein. Sphingosine-1-phosphate (S1P)-a lysosphingolipid exerting its biological activity via binding to specific G protein-coupled receptors and regulating a wide array of biological responses in a variety of different organs and tissues including the cardiovascular system-has been identified as an integral constituent of HDL particles. In the present review, we discuss current evidence from epidemiological studies, experimental approaches in vitro, and animal models of atherosclerosis, suggesting that S1P contributes to atheroprotective effects exerted by HDL particles.

Topics: Animals; Atherosclerosis; Biomarkers; Cholesterol, HDL; Humans; Lipoproteins, HDL; Lysophospholipids; Protective Factors; Risk Factors; Signal Transduction; Sphingosine

Atherosclerosis is the major cause of mortality in the developed countries. Although presently known risk factors have some predictive value for the disease, a major part of the variability in this process remains unexplained. It is extremely important to find new approaches for better understanding of the disease and for treating it. Exploration of the sphingolipid metabolism is one of these approaches. Sphingolipids are a large class of lipids with structural and signaling functions. Recent researches indicated that these lipids play important roles in the development of atherosclerosis. In this chapter, we summarized the major findings in the field.

Topics: Animals; Atherosclerosis; Cardiovascular Agents; Drug Design; Humans; Lysophospholipids; Molecular Targeted Therapy; Signal Transduction; Sphingolipids; Sphingomyelins; Sphingosine

The review will address the potential roles of apolipoprotein M (apoM) as a carrier protein and modulator of sphingosine-1-phosphate (S1P) bioactivity.. Recombinant apoM can bind small lipids such as retinoic acid, oxidized phospholipids, and S1P. Thus, the effects of apoM may be pleiotrophic. The S1P binding ability of apoM has biological impact. ApoM-bound S1P can activate S1P1 receptors on endothelial cells and deficiency of apoM abolishes the presence of S1P in HDL. In mice, the lack of apoM causes dysfunctional endothelial barrier function in the lungs. In humans, sepsis that is characterized by impaired endothelial function is associated with low plasma apoM.. Plasma apoM is mainly bound to HDL. The roles of apoM in atherosclerosis and lipoprotein metabolism have been given much attention. New in the field is the discovery of apoM as a chaperone for S1P. S1P is a bioactive lipid with effects on angiogenesis, lymphocyte trafficking, endothelial cell migration, and inflammation. A drug targeting the S1P-system (fingolimod) is now used for treatment of multiple sclerosis. It improves the blood-brain barrier and inhibits migration of lymphocytes into the brain. Further exploration of the apoM/S1P axis may uncover its potential as a biomarker and target for new treatments.

Topics: Animals; Apolipoproteins; Apolipoproteins M; Atherosclerosis; Endothelial Cells; Humans; Lipid Metabolism; Lipocalins; Lipoproteins, HDL; Lysophospholipids; Protein Binding; Sepsis; Sphingosine

The absolute level of HDL cholesterol (HDL-C) may not be the only criterion contributing to their antiatherothrombotic effects. This review focuses on evidence in support of the concept that HDL-bound sphingosine-1-phosphate (S1P) plays a role in different HDL atheroprotective properties and may represent a potential target for therapeutic interventions.. Recent large randomized clinical trials testing the hypothesis of raising HDL-C with niacin and dalcetrapib in statin-treated patients failed to improve cardiovascular outcomes. Emerging evidence suggests that many of the cardioprotective functions of HDL, such as vasodilation, angiogenesis and endothelial barrier function, protection against ischemia/reperfusion injury, and inhibition of atherosclerosis, may be attributable to its S1P cargo. HDL-associated S1P may represent a future therapeutic target.. HDL functionality is affected by its composition and there is evidence to suggest S1P plays a role in some of HDL's functions and atheroprotective properties.

Topics: Animals; Atherosclerosis; Cardiotonic Agents; Cholesterol, HDL; Coronary Artery Disease; Drug Therapy, Combination; Humans; Indoles; Lysophospholipids; Niacin; Randomized Controlled Trials as Topic; Sphingosine; Treatment Outcome

Sphingolipids have been recently elucidated to be not only mere components of the plasma membrane but also bioactive mediators which can induce various biological responses. Among these lipids, sphingomyelin(SM) and sphingosine 1-phosphate (Sph-1-P) are proposed to be involved in the pathogenesis of atherosclerosis: SM is abundant in atherosclerotic lesions and Sph-1-P is bound to HDL and attributes to the anti-atherosclerotic properties of HDL at least partly. Therefore, Sph-1-P and SM can be useful biomarkers for atherosclerotic disorders. However, at present, the measurement of Sph-1-P and SM levels has not been brought into clinical practice, yet. The main obstacle is the difficulty in measuring these sphingolipids precisely, rapidly, and conveniently. Recently, we have developed new methods for measuring Sph-1-P (HPLC method) and SM (enzymatic method). These methods are easy to be introduced into clinical laboratory testing because they do not need any special techniques and equipment. With this method for SM, we have demonstrated that the SM concentration was significantly higher in subjects with acute coronary syndrome. In this paper, we reviewed the possibility of sphingolipids as biomarkers for atherosclerotic disorders.

Topics: Acute Coronary Syndrome; Atherosclerosis; Biomarkers; Humans; Lysophospholipids; Sex Characteristics; Sphingolipids; Sphingosine

Sphingosine 1-phosphate (S1P) is a lipid mediator produced from sphingomyelin by the sequential enzymatic actions of sphingomyelinase, ceramidase, and sphingosine kinase. Five subtypes of cell surface G-protein-coupled receptors, S1P(1-5), mediate the actions of S1P in various organs systems, most notably cardiovascular, immune, and central nervous systems. S1P is enriched in blood and lymph but is present at much lower concentrations in interstitial fluids of tissues. This vascular S1P gradient is important for the regulation of trafficking of various immune cells. FTY720, which was recently approved for the treatment of relapsing-remitting multiple sclerosis, potently sequesters lymphocytes into lymph nodes by functionally antagonizing the activity of the S1P(1) receptor. S1P also plays critical roles in the vascular barrier integrity, thereby regulating inflammation, tumor metastasis, angiogenesis, and atherosclerosis. Recent studies have also revealed the involvement of S1P signaling in coagulation and in tumor necrosis factor α-mediated signaling. This review highlights the importance of S1P signaling in these inflammatory processes as well as the contribution of each receptor subtype, which exhibits both cooperative and redundant functions.

Topics: Animals; Atherosclerosis; Blood Coagulation; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Inflammation; Lymph Nodes; Lymphocytes; Lysophospholipids; Multiple Sclerosis; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Propylene Glycols; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Tumor Necrosis Factor-alpha

This review provides a summary of recent research on the role of high-density lipoprotein (HDL)/apolipoprotein A-I cholesterol efflux and immune cell function. Plasma concentrations of HDL have been known to inversely correlate with risk for coronary vascular disease. Bulk transport of HDL cholesterol from the peripheral tissues to the liver is a major pathway, termed reverse cholesterol transport, responsible for maintaining whole body cholesterol homeostasis. In addition to participating in this pathway, HDL and apolipoprotein A-I exert anti-inflammatory effects through different pathways. One pathway that seems to be important in atherosclerosis and autoimmunity is its role in modulation of T cell activation. HDL/apolipoprotein A-I helps regulate cell signaling by accepting membrane cholesterol from ATP binding cassette transporter A1 on immune cells and, thereby, fine tuning the amount of cholesterol present in plasma membrane lipid rafts.

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Autoimmunity; Biological Transport; Cholesterol; Homeostasis; Humans; Inflammation; Lipoproteins, HDL; Lymphocyte Activation; Lysophospholipids; Membrane Microdomains; Sphingosine; T-Lymphocytes

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

Sphingolipids have emerged as key signaling molecules involved in the regulation of a variety of cellular functions including cell growth and differentiation, proliferation and apoptotic cell death. Sphingolipids in blood constitute part of the circulating lipoprotein particles (HDL, LDL and VLDL), carried by serum albumin and also present in blood cells and platelets. Recent lipidomic and proteomic studies of plasma lipoproteins have provided intriguing data concerning the protein and lipid composition of lipoproteins in the context of disease. Sphingolipids have been implicated in several diseases such as cancer, obesity, atherosclerosis and sphingolipidoses; however, efforts addressing blood sphingolipidomics are still limited. The development of methods to determine levels of circulating bioactive sphingolipids in humans and validation of these methods to be a routine clinical laboratory test could be a pioneering approach to diagnose disease in the population. This approach would probably evolve to be analogous in implication to determining "good" and "bad" cholesterol and triglyceride levels in lipoprotein classes.

Topics: Animals; Apoptosis; Atherosclerosis; Blood Cells; Coronary Disease; Diabetes Mellitus, Type 2; Homeostasis; Humans; Inflammation; Lipid Metabolism, Inborn Errors; Lipoproteins; Lysophospholipids; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingosine

Atherosclerosis is the major cause of cardiovascular morbidity and mortality. A multitude of pro-atherogenic mediators are known liable for the initiation and progression of atherogenic vascular lesions. Only few endogenous molecules are known so far with cardiovascular protective properties, whereas high-density lipoprotein (HDL) is one of the most important. Beside cholesterol efflux, many pleiotropic cell-mediated functions of HDL are known so far. HDL is a spherical particle that contains different proteins and lipids. Especially sphingolipids, like sphingosine-1-phosphate (S1P), has gained great attention. The HDL associated S1P seems to be responsible for many of the pleiotropic effects of HDL by activating special S1P receptors. This review focuses on HDL associated sphingolipids as mediators of known protective pleiotropic effects of HDL and their possible therapeutic relevance.

Topics: Apoptosis; Atherosclerosis; Cell Adhesion; Humans; Lipoproteins, HDL; Lysophospholipids; Neovascularization, Pathologic; Receptors, Lysosphingolipid; Sphingolipids; Sphingosine

Plasma high-density lipoprotein (HDL) is a potent anti-atherogenic factor, a critical role of which is thought to be reverse cholesterol transport through the lipoprotein-associated apolipoprotein A-I (apoA-I). HDL also carries a potent bioactive lipid mediator, sphingosine 1-phophate (S1P), which exerts diverse physiological and pathophysiological actions in a variety of biological systems, including the cardiovascular system. In addition, HDL-associated apoA-I is known to stimulate intracellular signaling pathways unrelated to transporter activity. Mounting evidence indicates that multiple antiatherogenic or anti-inflammatory actions of HDL independent of cholesterol metabolism are mediated by the lipoprotein-associated S1P through S1P receptors and by apoA-I through scavenger receptor class B type I.

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; Cardiovascular System; Endothelial Cells; Humans; Lipoproteins, HDL; Lysophospholipids; Receptors, Lysosphingolipid; Scavenger Receptors, Class B; Signal Transduction; Sphingosine

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid that is critical in the development of blood vessels, and in the adult regulates vascular functions including vascular tone, endothelial integrity, and angiogenesis. Further, S1P may regulate arterial lesions in disease and after injury by controlling leukocyte recruitment and smooth muscle cell functions.

Topics: Animals; Arterial Occlusive Diseases; Arteries; Atherosclerosis; Endothelial Cells; Humans; Lysophospholipids; Receptors, Lysosphingolipid; 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 typical pathological feature of atherosclerosis is inflammation. In the last years, it has become evident that inhibition of inflammation is one important therapeutic option in atherosclerosis. Recently, sphingolipid sphingosine-1-phosphate (S1P) was identified as a crucial molecule with potent anti-inflammatory properties. Indeed, S1P activates various G protein-coupled receptors, namely S1P1-S1P5. In the vasculature, mainly S1P1-3 receptors are present. FTY720, after phosphorylation to FTY720-P, is an orally active S1P mimetic. FTY720 has been developed for therapy in the field of autoimmune diseases and organ transplantation. In analogy to S1P, FTY720 shows potent anti-inflammatory effects and several groups have tested the in vivo effects of FTY720 on the progression of inflammatory vascular diseases. They could show that S1P receptor activation might lead to a partial inhibition of the progression of atherosclerotic lesions. S1P receptor activation therefore might be a concept for anti-inflammatory drug treatment. However, it is not clear how S1P and FTY720 exactly act on vascular inflammation. This review article gives a brief overview over the known actions of S1P in vascular inflammatory disease.

Topics: Animals; Atherosclerosis; Blood Vessels; Endothelial Cells; Humans; Inflammation; Lysophospholipids; Myocytes, Smooth Muscle; Receptors, Lysosphingolipid; Sphingosine

Sphingosine 1-phosphate (S1P) is concentrated in lipoprotein, especially high density lipoprotein (HDL), in plasma. We characterized the role of HDL-associated S1P in HDL-induced anti-atherogenic effects. HDL-associated S1P mediated HDL-induced stimulation of proliferation, migration and inhibition of apoptosis through S1P specific receptors S1P1 and/or S1P3 in endothelial cells. On the other hand, HDL-induced nitric oxide production and inhibition of adhesion molecule expression were mediated by two pathways, i.e, HDL-associated apoprotein A-I, A-II/SR-BI and S1P/S1P receptors in endothelial cells. Thus, in endothelial cells, HDL-associated S1P is a key player of HDL-induced anti-atherogenic effects.

Topics: Atherosclerosis; Biomarkers; Endothelial Cells; Humans; Lipoproteins, HDL; Lysophospholipids; Receptors, Lysosphingolipid; 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

Atherosclerosis (AS) is a chronical pathological process of the arterial narrows due to the AS plaque formation. The aim of this study was to explore the therapeutic effect and the underlying mechanism of Floralozone on experimental atherosclerotic model rats. Experimental atherosclerotic model rats were induced by the right carotid artery balloon injury and intraperitoneal injection of vitamin D3 in rats after 4 weeks high-fat diet. The results exhibited that Floralozone could ameliorate vascular injury and vasorelaxation of descending aortas and increase the superoxide dismutase activity and the expression of sphingosine 1-phosphate (S1P) 1 and reduce the intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, interleukin (IL)-1, IL-6 level, and the malondialdehyde activity in experimental atherosclerotic rats. However, Fingolimod, an S1P1 inhibitor, could reverse these Floralozone effects in experimental atherosclerotic rats. Our results indicated that Floralozone could inhibit the atherosclerotic plaque formation and improves arterial stenosis and reduces endothelial dysfunction in experimental atherosclerotic rats, which might be involved with S1P1 enhancement.

Topics: Animals; Anti-Inflammatory Agents; Aromatherapy; Atherosclerosis; Balloon Occlusion; Carotid Arteries; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Flavoring Agents; Lysophospholipids; Male; Plant Extracts; Plaque, Atherosclerotic; Rats; Rats, Sprague-Dawley; Retinal Artery; Sphingosine; Sphingosine-1-Phosphate Receptors; Vasodilation

Studies have shown that apolipoprotein M (apoM), the main carrier of sphingosine-1-phosphate (S1P), is closely related to lipid metabolism and inflammation. While there are many studies on apoM and lipid metabolism, little is known about the role of apoM in inflammation. Atherosclerosis is a chronic inflammatory process. To clarify what role apoM plays in atherosclerosis, we used oxidized low-density lipoprotein (ox-LDL) to induce an inflammatory model of atherosclerosis. Our preliminary results indicate that ox-LDL upregulates the expression of S1P receptor 2 (S1PR2) in human umbilical vein endothelial cells (HUVECs). Ox-LDL-induced HUVECs were treated with apoM-bound S1P (apoM-S1P), free S1P or apoM, and apoM-S1P was found to significantly inhibit the expression of inflammatory factors and adhesion molecules. In addition, apoM-S1P inhibits ox-LDL-induced cellular inflammation via S1PR2. Moreover, apoM-S1P induces phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt, preventing nuclear translocation of nuclear factor-κB (NF-κB). PI3K-specific inhibitors and Akt inhibitors suppress apoM-S1P/S1PR2-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) release and affect nuclear translocation of NF-κB. In conclusion, the results demonstrate for the first time that apoM-S1P inhibits ox-LDL-induced inflammation in HUVECs via the S1PR2-mediated PI3K/Akt signaling pathway. This finding may aid in the development of new treatments for atherosclerosis.

Topics: Apolipoproteins M; Atherosclerosis; Cells, Cultured; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lipoproteins, LDL; Lysophospholipids; Models, Biological; Phosphatidylinositol 3-Kinase; Protein Binding; Proto-Oncogene Proteins c-akt; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Chronic kidney disease is characterized by uremia and causes premature death, partly due to accelerated atherosclerosis. Apolipoprotein (apo) M is a plasma carrier protein for the lipid sphingosine-1-phosphate (S1P). The Apom-S1P complex associates with HDL, and may contribute to its anti-atherosclerotic effects. The role of Apom/S1P in atherosclerosis is presently controversial and has not been explored in a uremic setting. We aimed to explore whether plasma concentrations of Apom/S1P are altered by uremia and whether Apom overexpression or deficiency affects classical and uremic atherosclerosis.. Mild to moderate uremia was induced by subtotal nephrectomy (NX) in 86-92 Apoe-deficient mice that were either Apom-wild type, Apom-deficient, or overexpressed Apom (∼10 fold). The effects of uremia on plasma Apom/S1P and atherosclerosis were evaluated and compared to non-nephrectomized controls.. Uremia increased plasma Apom by ∼25%, but not S1P. Plasma S1P was elevated by ∼300% in mice overexpressing Apom, and decreased by ∼25% in Apom-deficient mice. Apom overexpression augmented aortic root atherosclerosis and plasma cholesterol. In contrast, aortic arch atherosclerosis was unaffected by the Apom genotype. There was no effect of Apom-deficiency or Apom overexpression on uremic atherosclerosis.. This study highlights the complexity of Apom/S1P in atherosclerosis and challenges the notion that the Apom/S1P complex is anti-atherogenic, at least in Apoe-deficient mice.

Topics: Animals; Aortic Diseases; Apolipoproteins M; Atherosclerosis; Cholesterol; Disease Models, Animal; Female; Genetic Predisposition to Disease; Humans; Lysophospholipids; Mice, Inbred C57BL; Mice, Knockout, ApoE; Nephrectomy; Phenotype; Plaque, Atherosclerotic; Sphingosine; Uremia

Atherosclerotic changes of arteries are the leading cause for deaths in cardiovascular disease and greatly impair patient's quality of life. Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that regulates potentially pro-as well as anti-atherogenic processes. Here, we investigate whether serum-S1P concentrations are associated with peripheral artery disease (PAD) and carotid stenosis (CS).. Serum was sampled from blood donors (controls, N = 174) and from atherosclerotic patients (N = 132) who presented to the hospital with either clinically relevant PAD (N = 102) or CS (N = 30). From all subjects, serum-S1P was measured by mass spectrometry and blood parameters were determined by routine laboratory assays. When compared to controls, atherosclerotic patients before invasive treatment to restore blood flow showed significantly lower serum-S1P levels. This difference cannot be explained by risk factors for atherosclerosis (old age, male gender, hypertension, hypercholesteremia, obesity, diabetes or smoking) or comorbidities (Chronic obstructive pulmonary disease, kidney insufficiency or arrhythmia). Receiver operating characteristic curves suggest that S1P has more power to indicate atherosclerosis (PAD and CS) than high density lipoprotein-cholesterol (HDL-C). In 35 patients, serum-S1P was measured again between one and six months after treatment. In this group, serum-S1P concentrations rose after treatment independent of whether patients had PAD or CS, or whether they underwent open or endovascular surgery. Post-treatment S1P levels were highly associated to platelet numbers measured pre-treatment.. Our study shows that PAD and CS in humans is associated with decreased serum-S1P concentrations and that S1P may possess higher accuracy to indicate these diseases than HDL-C.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Atherosclerosis; Blood Coagulation; Carotid Stenosis; Case-Control Studies; Cholesterol, HDL; Cohort Studies; Female; Humans; Lipoproteins, HDL; Lysophospholipids; Male; Middle Aged; Peripheral Arterial Disease; Prognosis; Regression Analysis; Risk Factors; ROC Curve; Signal Transduction; Sphingosine; Young Adult

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

The sphingosine 1-phosphate receptor 1 (S1P1) is abundant in endothelial cells, where it regulates vascular development and microvascular barrier function. In investigating the role of endothelial cell S1P1 in adult mice, we found that the endothelial S1P1 signal was enhanced in regions of the arterial vasculature experiencing inflammation. The abundance of proinflammatory adhesion proteins, such as ICAM-1, was enhanced in mice with endothelial cell-specific deletion of S1pr1 and suppressed in mice with endothelial cell-specific overexpression of S1pr1, suggesting a protective function of S1P1 in vascular disease. The chaperones ApoM(+)HDL (HDL) or albumin bind to sphingosine 1-phosphate (S1P) in the circulation; therefore, we tested the effects of S1P bound to each chaperone on S1P1 signaling in cultured human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs to ApoM(+)HDL-S1P, but not to albumin-S1P, promoted the formation of a cell surface S1P1-β-arrestin 2 complex and attenuated the ability of the proinflammatory cytokine TNFα to activate NF-κB and increase ICAM-1 abundance. Although S1P bound to either chaperone induced MAPK activation, albumin-S1P triggered greater Gi activation and receptor endocytosis. Endothelial cell-specific deletion of S1pr1 in the hypercholesterolemic Apoe(-/-) mouse model of atherosclerosis enhanced atherosclerotic lesion formation in the descending aorta. We propose that the ability of ApoM(+)HDL to act as a biased agonist on S1P1 inhibits vascular inflammation, which may partially explain the cardiovascular protective functions of HDL.

Topics: Animals; Apolipoproteins; Apolipoproteins M; Atherosclerosis; Disease Models, Animal; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Lipocalins; Lipoproteins, HDL; Lysophospholipids; Mice; Mice, Knockout; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Vasculitis

Natural killer T (NKT) cells are unique T lymphocytes that recognize glycolipid antigen and produce various cytokines. NKT cells accelerate atherosclerosis in mice. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and regulates T-lymphocyte trafficking. We aimed to determine the effects of S1P on the production of proinflammatory cytokine, tumor necrosis factor (TNF)-α, in NKT cell hybridomas and mouse NKT cells.. NKT cell hybridomas and sorted mouse NKT cells were stimulated with S1P and α-galactosylceramide (α-GalCer), the major ligand to produce cytokines in NKT cells. TNF-α mRNA expression and protein production were determined by real-time PCR and ELISA, respectively. Cell migration was assayed using chemotaxicell. Plasma S1P was measured using HPLC.. Hybridomas expressed S1P receptors, S1P1, S1P2, and S1P4. S1P and α-GalCer increased TNF-α mRNA expression and protein production. S1P enhanced TNF-α induction by α-GalCer. S1P receptor antagonists decreased the TNF-α mRNA expression induced by S1P. FTY720, an immunosuppressive S1P receptor modulator, also decreased the TNF-α mRNA expression. The migration of NKT cell hybridomas was increased by S1P. FTY720 reduced the migration induced by S1P. S1P also increased the TNF-α mRNA expression in mouse NKT cells. Plasma TNF-α levels in patients with high plasma S1P (≥500 nmol/l) were higher than those in patients with low S1P (<500 nmol/l).. S1P binds to S1P receptors in NKT cells and enhances TNF-α production. TNF-α overproduction may induce atherogenic inflammatory responses. S1P may serve as a novel therapeutic target for amelioration of vascular inflammatory diseases.

Topics: Animals; Atherosclerosis; Cell Line, Tumor; Chemotaxis, Leukocyte; Coculture Techniques; Female; Humans; Hybridomas; Immunologic Factors; Inflammation; Inflammation Mediators; Lymphocyte Activation; Lysophospholipids; Mice, Inbred C57BL; Natural Killer T-Cells; Plasminogen Activator Inhibitor 1; Rats; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Time Factors; Tumor Necrosis Factor-alpha

Sphingosine 1-phosphate (S1P) is a vasoprotective lipid mediator that is mainly carried on HDL in the circulation and several anti-atherosclerotic properties of HDL is considered to be ascribed to S1P. Since S1P riding on HDL was recently shown to bind to apolipoprotein M (apoM), which is derived from liver, we analyzed the possible involvement of liver in S1P metabolism.. Using adenoviruses, we overexpressed apoM in HepG2 cells and mice livers and found that both the medium/plasma and cell/liver S1P contents increased. Among lipoprotein subclasses, S1P contents increased mainly in HDL fractions. On the other hand, hepatectomy resulted in the reduction of plasma S1P levels in mice. The incubation of S1P in the conditional medium of apoM-overexpressing HepG2 cells interfered with S1P degradation. Furthermore, adenoviral hepatic overexpression of apoM resulted in increase in the S1P level of plasma but not of blood cells, while combination of hepatic apoM overexpression and intraperitoneal administration of C₁₇-sphingosine resulted in the increase in the C₁₇-S1P level both in livers and in plasma, but again not in blood cells.. Livers are involved in S1P dynamism, and it was suggested that apoM, produced from livers, increases circulating plasma S1P by augmenting the S1P output from livers and modifies extracellular S1P metabolism.

Topics: Adenoviridae; Animals; Apolipoproteins; Apolipoproteins M; Atherosclerosis; Cholesterol, HDL; Cholesterol, VLDL; Gene Expression; Hep G2 Cells; Hepatectomy; Humans; Lipocalins; Liver; Lysophospholipids; Mice; Mice, Inbred C57BL; Sphingosine; Triglycerides

Altered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/-)) deficiency on leukocyte subsets relevant to atherosclerosis.. LDL receptor deficient mice that were transplanted with Sgpl1(-/-) bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1(-/-) chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response.. Here we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.

Topics: Aldehyde-Lyases; Animals; Atherosclerosis; Bone Marrow Cells; Cell Differentiation; Female; Hematopoiesis; Lymphocyte Count; Lymphopenia; Lysophospholipids; Macrophages; Mice; Mice, Knockout; Neutrophils; Phenotype; Plaque, Atherosclerotic; Receptors, LDL; Sphingosine; Spleen

Serotonin stored in platelets is released into plasma on aggregation and activation in atherosclerotic diseases. Sphingosine 1-phosphate (S1P) in plasma is mainly derived from red blood cells and is responsible for the production of nitric oxide in endothelial cells and protects vasculature. The purpose of this study was to investigate the plasma levels of serotonin, S1P, and their clinical relationships with vascular endothelial function in patients with early atherosclerosis.. Blood was withdrawn from patients with low-to-moderate risks of atherosclerotic diseases (n=49, 39 ± 7 years). Platelet-poor plasma was immediately centrifuged. Serotonin levels in plasma were measured with high-performance liquid chromatography. S1P levels in plasma were measured by high-performance liquid chromatography after fluorescent derivatization with o-phthaldialdehyde. Endothelial function was assessed by endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent dilation was measured by glycerol trinitrate-induced dilation using an ultrasound system.. Plasma serotonin was inversely correlated with the FMD value (r=-0.287, P<0.05). Fourteen patients with dyslipidemia, who had not shown improvements after lifestyle modifications, were subsequently treated with rosuvastatin (2.5 mg/day). After 4 weeks of treatment, rosuvastatin improved lipid profiles. Rosuvastatin increased FMD, whereas glycerol trinitrate-induced dilation was unchanged. Notably, percentage decrease in plasma serotonin was inversely correlated with percentage increase in plasma S1P (r=-0.557, P<0.05).. Plasma serotonin was inversely correlated with FMD and a decrease in plasma serotonin was inversely correlated with an increase in plasma S1P after statin treatment. The results suggested that plasma levels of serotonin and S1P may be useful for the assessment of endothelial function of patients with low-to-moderate risks of atherosclerotic diseases.

Topics: Adult; Atherosclerosis; Cholesterol; Chromatography, High Pressure Liquid; Endothelium, Vascular; Female; Humans; Lysophospholipids; Male; Middle Aged; Serotonin; Serotonin Receptor Agonists; Sphingosine; Vasodilation

Sphingosine 1-phosphate (S1P) mediates critical physiological responses by its binding to G protein-coupled receptor (GPCR) subtypes, known as S1P receptors. Five distinct mammalian S1P receptors, designated S1P1-5 have been identified, each with a different cellular pattern of expression which influences the responses to S1P. In this review, we briefly outline our understanding of the modes of action and the roles of S1P receptors in the regulation of physiological and pathological functions in the cardiovascular, immune and central nervous system.

Topics: Animals; Atherosclerosis; Cardiovascular System; Cell Movement; Humans; Lymphocytes; Lysophospholipids; Macrophage Activation; Macrophages; Mammals; Mice; Mice, Knockout; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Nerve Tissue Proteins; Neurogenesis; Receptors, Lysosphingolipid; Second Messenger Systems; Sphingosine

Sphingosine 1-phosphate (S1P) - a constitutive component of human plasma - is implicated as a signalling molecule in the regulation of cell adhesion molecules (CAM) in vascular endothelial cells (EC), but the degree of the S1P-induced expression of CAM and the involvement of the S1P(1) receptor are still ambiguous. Here, we report that S1P, when added to vascular EC in the absence of other stimuli, induced a strictly proportional and concentration-dependent expression of E-selectin mRNA, of E-selectin protein and of the number of adhering THP-1 monocytes to EC. Experiments with exogenous [(3)H]S1P showed a multi-exponential influx kinetic of intracellular uptake of [(3)H]S1P up to a steady state level over 2h. This process could be inhibited or enhanced by various synthetic modulators targeting both, S1P(1) receptor-dependent (Akt, ERK1/2) as well as independent DMS-sensitive pathways. The S1P(1) receptor signalling was shown to drive the sphingosine kinase - the rate limiting enzyme for the formation of S1P - to a higher or lower activity. Furthermore, S1P as an intracellular messenger induced the phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB and in turn the expression of E-selectin and monocyte adhesion. Taken together, these results suggest that the physiologically controlled variation in intracellular S1P concentrations may represent a novel not yet known mechanism of fine-tuning the expression of proinflammatory and atherogenic E-selectin cell adhesion molecule by vascular endothelial cells.

Topics: Atherosclerosis; Cell Adhesion; Cell Line; E-Selectin; Endothelial Cells; Humans; Inflammation Mediators; Intracellular Fluid; Lysophospholipids; Monocytes; RNA, Messenger; Signal Transduction; Sphingosine

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that has pleiotropic effects in a variety of cell types including ECs, SMCs, and macrophages, all of which are central to the development of atherosclerosis. It may therefore exert stimulatory and inhibitory effects on atherosclerosis. Here, we investigated the role of the S1P receptor S1PR2 in atherosclerosis by analyzing S1pr2-/- mice with an Apoe-/- background. S1PR2 was expressed in macrophages, ECs, and SMCs in atherosclerotic aortas. In S1pr2-/-Apoe-/- mice fed a high-cholesterol diet for 4 months, the area of the atherosclerotic plaque was markedly decreased, with reduced macrophage density, increased SMC density, increased eNOS phosphorylation, and downregulation of proinflammatory cytokines compared with S1pr2+/+Apoe-/- mice. Bone marrow chimera experiments indicated a major role for macrophage S1PR2 in atherogenesis. S1pr2-/-Apoe-/- macrophages showed diminished Rho/Rho kinase/NF-κB (ROCK/NF-κB) activity. Consequently, they also displayed reduced cytokine expression, reduced oxidized LDL uptake, and stimulated cholesterol efflux associated with decreased scavenger receptor expression and increased cholesterol efflux transporter expression. S1pr2-/-Apoe-/- ECs also showed reduced ROCK and NF-κB activities, with decreased MCP-1 expression and elevated eNOS phosphorylation. Pharmacologic S1PR2 blockade in S1pr2+/+Apoe-/- mice diminished the atherosclerotic plaque area in aortas and modified LDL accumulation in macrophages. We conclude therefore that S1PR2 plays a critical role in atherogenesis and may serve as a novel therapeutic target for atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Becaplermin; Cells, Cultured; Female; Lysophospholipids; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Smooth Muscle; NF-kappa B; Plaque, Atherosclerotic; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Receptors, Lysosphingolipid; rho-Associated Kinases; Sphingosine; Sphingosine-1-Phosphate Receptors

Although it is well known that sphingosine-1-phosphate (S1P), which induces many biological responses, is present in plasma and is mainly released from activated platelets, little is known whether the release of S1P is increased when platelets are activated in the hypercholesterolemic condition, and what are the roles of increased S1P generation in the development or progression of the atherosclerosis. Results show that 0.5% cholesterol diet for 16 weeks induces platelet hyperaggregability to low doses of agonists as well as development of hypercholesterolemic atherosclerosis in the rabbits. The generation and released level of S1P were significantly increased in the hypersensitized platelets and blood plasma in hypercholesterolemic rabbits. We also demonstrated that S1P increased VSMC proliferation via endothelial differentiation gene (EDG)-1 receptor dependent pathway. Our results indicate that release of S1P from activated platelets was increased by enhanced platelet sensitivity in hypercholesterolemia, which potentiated the ox-LDL-induced VSMC proliferation via EDG-1 receptor pathway.

Topics: Animals; Aorta; Aorta, Thoracic; Arachidonic Acid; Atherosclerosis; Blood Platelets; Cell Proliferation; Cells, Cultured; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Collagen; Hypercholesterolemia; Lipoproteins, LDL; Lysophospholipids; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Platelet Aggregation; Rabbits; Receptors, Lysosphingolipid; Sphingosine; Thrombin; Triglycerides

Vascular inflammation is a major atherogenic factor and Toll-like receptor (TLR) 2 ligands, including bacterial and serum lipoproteins, seem to be involved in atherogenesis. On this basis, we analysed the effect of lipoproteins and different lipid components on TLR2-dependent signalling.. In TLR2-transfected human embryonic kidney 293 cells and human monocytes, oxidized low-density lipoproteins inhibited nuclear factor (NF)-kappaB-driven transcriptional activity and chemokine gene expression in response to TLR2 ligands. Sphingosine 1-phosphate (S1P) and oxidized palmitoyl-arachidonoyl-phosphatidylcholine, but not lipoprotein-carried lysophospholipids, inhibited TLR2 activation. Silencing experiments in TLR2-transfected 293 cells showed that the S1P-mediated attenuation effect is mediated by S1P receptors type 1 and type 2. To address the physiological significance of these findings, additional experiments were performed in human peripheral blood monocytes and monocyte-derived macrophages. In both cell types, S1P selectively attenuated TLR2 signalling, as NF-kappaB and extracellular signal-regulated kinase activation, but not c-Jun amino terminal kinase phosphorylation, were inhibited by physiologically relevant concentrations of S1P. Moreover, the attenuation of TLR2 signalling was partially reverted by pharmacological inhibition of phosphoinositide 3-kinase (PI3K) and Ras pathways. In addition, S1P inhibited the chemokine gene expression elicited by TLR2, but not by TLR4 ligands.. These findings disclose a cross-talk mechanism between lipoprotein components and TLR in which engagement of S1P receptors exert selective attenuation of TLR2-dependent activation via PI3K and Ras signalling. A corollary to these data is that the negative cross-talk of S1P receptors and TLR2 signalling might be involved in the atheroprotective effects of S1P.

Topics: Atherosclerosis; Cell Line; Chemokines; Enzyme Inhibitors; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Lysophospholipids; NF-kappa B; Phagocytes; Phosphatidylcholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; ras Proteins; Receptors, Lysosphingolipid; RNA Interference; RNA, Small Interfering; Signal Transduction; Sphingosine; Time Factors; Toll-Like Receptor 2; Transcription, Genetic; Transfection

Reconstituted high-density lipoprotein (rHDL) has been shown to produce a rapid regression of atherosclerosis in animal models and humans. Sphingosine-1-phosphate (S1P), which is a bioactive lipid in HDL, plays a role in mitogenesis, endothelial cell motility, and cell survival, as well as organization and differentiation into a vessel. In this study, we examined the direct role of a newly developed rHDL, [POPC(1-palmitoyl-2-oleoyl phosphatidylcholine)/S1P/apolipoproteinA-I(A-I)]rHDL containing S1P in tube formation in endothelial cells (ECs) as well as cholesterol efflux in macrophage. The effect of (POPC/S1P/A-I)rHDL on cholesterol efflux in macrophage was similar to that of conventional rHDL, (POPC/A-I)rHDL. In addition, (POPC/S1P/A-I)rHDL induced EC proliferation through the activation of phospho-Akt and phospho-extracellular-signal-regulated kinases (p-ERK) 1/2 and EC tube formation, and this effect was blocked by inhibitors of Akt, ERK and endothelial nitric-oxide synthase (eNOS). In addition, (POPC/S1P/A-I)rHDL-induced p-ERK1/2 activation and EC tube formation can be mainly attributed to S1P-stimulated signaling through S1P2 and S1P3 as determined by an anti-sense strategy. In conclusion, (POPC/S1P/A-I)rHDL induces cholesterol efflux independently of S1P but has additional S1P-mediated effects on EC tube formation mediated by Akt/ERK/NO through S1P2 and S1P3. In the future, these new discs may be useful for the treatment of atherosclerotic and ischemic cardiovascular disease, such as acute coronary syndrome and atherosclerosis obliterans.

Topics: Animals; Atherosclerosis; Cell Division; Cells, Cultured; CHO Cells; Cholesterol; Coronary Vessels; Cricetinae; Cricetulus; Endothelial Cells; Enzyme Inhibitors; Humans; In Vitro Techniques; Lipoproteins, HDL; Lysophospholipids; Macrophages; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Oligonucleotides, Antisense; Phosphatidylcholines; Proto-Oncogene Proteins c-akt; ras Proteins; Sphingosine

The sphingosine-1-phosphate (S1P) analogue FTY720 is a potent immunosuppressive agent currently in Phase III clinical trials for kidney transplantation. FTY720 traps lymphocytes in secondary lymphoid organs thereby preventing their migration to inflammatory sites. Previously, we have identified FTY720 as a potent activator of eNOS. As both inhibition of immune responses and stimulation of eNOS may attenuate atherosclerosis, we administered FTY720 to apolipoprotein E-/- mice fed a high-cholesterol diet.. FTY720 dramatically reduced atherosclerotic lesion volume (62.5%), macrophage (41.8%), and collagen content (63.5%) after 20 weeks of high-cholesterol diet. In isolated aortic segments and cultured vascular smooth muscle cell, FTY720 potently inhibited thrombin-induced release of monocyte chemoattractant protein-1. This effect was mediated by the S1P3 sphingolipid receptor as FTY720 had no effect on thrombin-induced monocyte chemoattractant protein-1 release in S1P3-/- mice. In contrast to S1P receptors on lymphocytes, FTY720 did not desensitize vascular S1P receptors as arteries from FTY720-treated mice retained their vasodilator response to FTY720-phosphate.. We suggest that FTY720 inhibits atherosclerosis by suppressing the machinery involved in monocyte/macrophage emigration to atherosclerotic lesions. As vascular S1P receptors remained functional under FTY720 treatment, S1P agonists that selectively target the vasculature and not the immune system may be promising new drugs against atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Cell Movement; Cells, Cultured; Cholesterol, Dietary; Cytokines; Disease Models, Animal; Fingolimod Hydrochloride; Gene Expression Regulation; Immunohistochemistry; Lysophospholipids; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Probability; Propylene Glycols; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sphingosine; Statistics, Nonparametric

Numerous in vitro studies suggest that sphingosine 1-phosphate (S1P), a bioactive lysosphingolipid associated with high-density lipoproteins, accounts at least partly for the potent antiinflammatory properties of high-density lipoprotein and, thereby, contributes to the antiatherogenic potential attributed to high-density lipoproteins. The present study was undertaken to investigate whether modulation of S1P signaling would affect atherosclerosis in a murine model of disease.. Low-density lipoprotein receptor-deficient mice on a cholesterol-rich diet were given FTY720, a synthetic S1P analogue, at low (0.04 mg/kg per day) or high (0.4 mg/kg per day) doses for 16 weeks. FTY720 dose-dependently reduced atherosclerotic lesion formation, both in the aortic root and brachiocephalic artery, and almost completely blunted necrotic core formation. Plasma lipids remained unchanged during the course of FTY720 treatment. However, FTY720 lowered blood lymphocyte count (at a high dose) and significantly interfered with lymphocyte function, as evidenced by reduced splenocyte proliferation and interferon-gamma levels in plasma. Plasma concentrations of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-6, IL-12, and regulated on activation normal T cell expressed and secreted were reduced by FTY720 administration. Moreover, lipopolysaccharide-elicited generation of nitrite/nitrate and IL-6--two markers of classical (M1) macrophage activation--was inhibited, whereas IL-4-induced production of IL-1-receptor antagonist, a marker of alternative (M2) macrophage activation, was augmented in peritoneal macrophages from FTY720-treated low-density lipoprotein receptor-deficient mice.. The present results demonstrate that an S1P analogue inhibits atherosclerosis by modulating lymphocyte and macrophage function, and these results are consistent with the notion that S1P contributes to the antiatherogenic potential of high-density lipoprotein.

Topics: Animals; Atherosclerosis; Cell Division; Cholesterol, HDL; Cytokines; Disease Models, Animal; Female; Fingolimod Hydrochloride; Immunosuppressive Agents; Lymphocyte Count; Lymphocytes; Lysophospholipids; Macrophages; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Propylene Glycols; Receptors, LDL; Signal Transduction; Sphingosine; Triglycerides

Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism.. ApoE-/- mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol (largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative (2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells (CD4+ CD44hi CD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.. FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Fingolimod Hydrochloride; Hypercholesterolemia; Immunosuppressive Agents; Lipid Metabolism; Lymphocyte Subsets; Lymphocytes; Lymphopenia; Lysophospholipids; Male; Mice; Mice, Knockout; Propylene Glycols; Sphingosine; Spleen

Topics: Animals; Atherosclerosis; Blood Vessels; Diabetes Mellitus, Type 1; Glucose; Humans; Lysophospholipids; Sphingosine