sphingosine-1-phosphate and Cardiovascular-Diseases

Sphingosine-1-phosphate (S1P) is an important sphingolipid molecule involved in regulating cardiovascular functions in physiological and pathological conditions by binding and activating the three G protein-coupled receptors (S1PR1, S1PR2, and S1PR3) expressed in endothelial and smooth muscle cells, as well as cardiomyocytes and fibroblasts. It exerts its actions through various downstream signaling pathways mediating cell proliferation, migration, differentiation, and apoptosis. S1P is essential for the development of the cardiovascular system, and abnormal S1P content in the circulation is involved in the pathogenesis of cardiovascular disorders. This article reviews the effects of S1P on cardiovascular function and signaling mechanisms in different cell types in the heart and blood vessels under diseased conditions. Finally, we look forward to more clinical findings with approved S1PR modulators and the development of S1P-based therapies for cardiovascular diseases.

Topics: Cardiovascular Diseases; Humans; Lysophospholipids; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors

The medical community recognizes sex-related differences in pathophysiology and cardiovascular disease outcomes (CVD), culminating with heart failure. In general, pre-menopausal women tend to have a better prognosis than men. Explaining why this occurs is not a simple matter. For decades, sex hormones like estrogens (Es) have been identified as one of the leading factors driving these sex differences. Indeed, Es seem protective in women as their decline, during and after menopause, coincides with an increased CV risk and HF development. However, clinical trials demonstrated that E replacement in post-menopause women results in adverse cardiac events and increased risk of breast cancer. Thus, a deeper understanding of E-related mechanisms is needed to provide a vital gateway toward better CVD prevention and treatment in women. Of note, sphingolipids (SLs) and their metabolism are strictly related to E activities. Among the SLs, ceramide and sphingosine 1-phosphate play essential roles in mammalian physiology, particularly in the CV system, and appear differently modulated in males and females. In keeping with this view, here we explore the most recent experimental and clinical observations about the role of E and SL metabolism, emphasizing how these factors impact the CV system.

Topics: Animals; Cardiovascular Diseases; Ceramides; Estrogens; Female; Humans; Lysophospholipids; Male; Mammals; Sex Characteristics; Sphingolipids; Sphingosine

Membrane phospholipid metabolism forms lysophospholipids, which possess unique biochemical and biophysical properties that influence membrane structure and dynamics. However, lysophospholipids also function as ligands for G-protein-coupled receptors that influence embryonic development, postnatal physiology, and disease. The 2 most well-studied species-lysophosphatidic acid and S1P (sphingosine 1-phosphate)-are particularly relevant to vascular development, physiology, and cardiovascular diseases. This review summarizes the role of lysophosphatidic acid and S1P in vascular developmental processes, endothelial cell biology, and their roles in cardiovascular disease processes. In addition, we also point out the apparent connections between lysophospholipid biology and the Wnt (int/wingless family) pathway, an evolutionarily conserved fundamental developmental signaling system. The discovery that components of the lysophospholipid signaling system are key genetic determinants of cardiovascular disease has warranted current and future research in this field. As pharmacological approaches to modulate lysophospholipid signaling have entered the clinical sphere, new findings in this field promise to influence novel therapeutic strategies in cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Endothelial Cells; Humans; Ligands; Lysophospholipids; Morphogenesis; Receptors, Lysophosphatidic Acid; Receptors, Lysophospholipid; Sphingosine; Sphingosine-1-Phosphate Receptors; Wnt Signaling Pathway

Sphingosine-1-phosphate (S1P) is a signaling lipid, synthetized by sphingosine kinases (SPHK1 and SPHK2), that affects cardiovascular function in various ways. S1P signaling is complex, particularly since its molecular action is reliant on the differential expression of its receptors (S1PR1, S1PR2, S1PR3, S1PR4, S1PR5) within various tissues. Significance of this sphingolipid is manifested early in vertebrate development as certain defects in S1P signaling result in embryonic lethality due to defective vasculo- or cardiogenesis. Similar in the mature organism, S1P orchestrates both physiological and pathological processes occurring in the heart and vasculature of higher eukaryotes. S1P regulates cell fate, vascular tone, endothelial function and integrity as well as lymphocyte trafficking, thus disbalance in its production and signaling has been linked with development of such pathologies as arterial hypertension, atherosclerosis, endothelial dysfunction and aberrant angiogenesis. Number of signaling mechanisms are critical - from endothelial nitric oxide synthase through STAT3, MAPK and Akt pathways to HDL particles involved in redox and inflammatory balance. Moreover, S1P controls both acute cardiac responses (cardiac inotropy and chronotropy), as well as chronic processes (such as apoptosis and hypertrophy), hence numerous studies demonstrate significance of S1P in the pathogenesis of hypertrophic/fibrotic heart disease, myocardial infarction and heart failure. This review presents current knowledge concerning the role of S1P in the cardiovascular system, as well as potential therapeutic approaches to target S1P signaling in cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Embryonic Development; Hemodynamics; Humans; Lysophospholipids; Neovascularization, Physiologic; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

There are many different types of cardiovascular diseases, which impose a huge economic burden due to their extremely high mortality rates, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator with paracrine and autocrine activities that acts through its cell surface S1P receptors (S1PRs) and intracellular signals. In the circulatory system, S1P is indispensable for both normal and disease conditions; however, there are very different views on its diverse roles, and its specific relevance to cardiovascular pathogenesis remains elusive. Here, we review the synthesis, release and functions of S1P, specifically detail the roles of S1P and S1PRs in some common cardiovascular diseases, and then address several controversial points, finally, we focus on the development of S1P-based therapeutic approaches in cardiovascular diseases, such as the selective S1PR1 modulator amiselimod (MT-1303) and the non-selective S1PR1 and S1PR3 agonist fingolimod, which may provide valuable insights into potential therapeutic strategies for cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Humans; Lysophospholipids; Models, Biological; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Topics: Animals; Apolipoproteins M; Autoimmune Diseases; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Central Nervous System; Drug Development; Fibrosis; Homeostasis; Humans; Immune System Phenomena; Lysophospholipids; Mice; Molecular Chaperones; Neurodegenerative Diseases; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine kinases (SphKs) catalyze the conversion of the sphingosine to the promitogenic/migratory product, sphingosine-1-phosphate (S1P). SphK/S1P pathway has been linked to the progression of cancer and various other diseases including allergic inflammatory disease, cardiovascular diseases, rejection after transplantation, the central nervous system, and virus infections. Therefore, SphKs represent potential new targets for developing novel therapeutics for these diseases. The history and development of SphK inhibitors are discussed, summarizing SphK inhibitors by their structures, and describing some applications of SphK inhibitors. We concluded: i) initial SphK inhibitors based on sphingosine have low specificity with several important off-targets. Identification the off-targets that would work synergistically with SphKs, and developing compounds that target the unique C4 domain of SphKs should be the focus of future studies. ii) The modifications of SphK inhibitors, which are devoted to increasing the selectivity to one of the two isoforms, now focus on the alkyl length, the spacer between the head and linker rings, and the insertion and the position of lipidic group in tail region. iii) SphK/S1P signaling pathway holds therapeutic values for many diseases. To find the exact function of each isoform of SphKs increasing the number of SphK inhibitor clinical trials is necessary.

Topics: Animals; Cardiovascular Diseases; Drug Discovery; Humans; Hypersensitivity; Lysophospholipids; Molecular Targeted Therapy; Neoplasms; Patents as Topic; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Signal Transduction; 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

Sphingosine kinases (isoforms SK1 and SK2) catalyse the formation of a bioactive lipid, sphingosine 1-phosphate (S1P). S1P is a well-established ligand of a family of five S1P-specific G protein coupled receptors but also has intracellular signalling roles. There is substantial evidence to support a role for sphingosine kinases and S1P in health and disease. This review summarises recent advances in the area in relation to receptor-mediated signalling by S1P and novel intracellular targets of this lipid. New evidence for a role of each sphingosine kinase isoform in cancer, the cardiovascular system, central nervous system, inflammation and diabetes is discussed. There is continued research to develop isoform selective SK inhibitors, summarised here. Analysis of the crystal structure of SK1 with the SK1-selective inhibitor, PF-543, is used to identify residues that could be exploited to improve selectivity in SK inhibitor development for future therapeutic application.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Inflammation; Lysophospholipids; Models, Molecular; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Receptors, G-Protein-Coupled; Signal Transduction; Sphingosine; Structure-Activity Relationship

Sphingolipids (SL) are both fundamental structural components of the eukaryotic membranes and signaling molecules that regulate a variety of biological functions. The highly-bioactive lipids, ceramide and sphingosine-1-phosphate, have emerged as important regulators of cardiovascular function in health and disease. In this review we discuss recent insights into the role of SLs, particularly ceramide and sphingosine-1-phosphate, in the pathophysiology of the cardiovascular system. We also highlight advances into the molecular mechanisms regulating serine palmitoyltransferase, the first and rate-limiting enzyme of de novo SL biosynthesis, with an emphasis on the recently discovered inhibitors of serine palmitoyltransferase, ORMDL and NOGO-B proteins. Understanding the molecular mechanisms regulating this biosynthetic pathway may lead to the development of novel therapeutic approaches for the treatment of cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Homeostasis; Humans; Lysophospholipids; Nogo Proteins; Sphingolipids; Sphingosine

The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL's anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL's protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL's biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Humans; Lipoproteins, HDL; Lysophospholipids; Serum Amyloid A Protein; Sphingosine

This review will address recent findings on apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) in lipid metabolism and inflammatory diseases.. ApoM's likely role(s) in health and disease has become more diverse after the discovery that apoM functions as a chaperone for S1P. Hence, apoM has recently been implicated in lipid metabolism, diabetes and rheumatoid arthritis through in-vivo, in-vitro and genetic association studies. It remains to be established to which degree such associations with apoM can be attributed to its ability to bind S1P.. The apoM/S1P axis and its implications in atherosclerosis and lipid metabolism have been thoroughly studied. Owing to the discovery of the apoM/S1P axis, the scope of apoM research has broadened. ApoM and S1P have been implicated in lipid metabolism, that is by modulating HDL particles. Also, the importance in regulating endothelial function is being investigated. Furthermore, both apoM and S1P have been linked to diabetes and glucose and insulin metabolism. Finally, genetic variations in the apoM gene are associated with lipid disturbances, diabetes and rheumatoid arthritis. These findings suggest not only diverse effects of apoM, but also the important question of whether apoM mainly acts as a S1P carrier, if apoM carries other substances with biological effects as well, or whether the apoM protein has effects on its own.

Topics: Animals; Apolipoproteins; Apolipoproteins M; Cardiovascular Diseases; Endothelial Cells; Humans; Lipid Metabolism; Lipocalins; Lysophospholipids; Metabolic Diseases; Sphingosine

Membrane sphingolipids are metabolized to sphingosine-1-phosphate (S1P), a bioactive lipid mediator that regulates many processes in vertebrate development, physiology, and pathology. Once exported out of cells by cell-specific transporters, chaperone-bound S1P is spatially compartmentalized in the circulatory system. Extracellular S1P interacts with five GPCRs that are widely expressed and transduce intracellular signals to regulate cellular behavior, such as migration, adhesion, survival, and proliferation. While many organ systems are affected, S1P signaling is essential for vascular development, neurogenesis, and lymphocyte trafficking. Recently, a pharmacological S1P receptor antagonist has won approval to control autoimmune neuroinflammation in multiple sclerosis. The availability of pharmacological tools as well as mouse genetic models has revealed several physiological actions of S1P and begun to shed light on its pathological roles. The unique mode of signaling of this lysophospholipid mediator is providing novel opportunities for therapeutic intervention, with possibilities to target not only GPCRs but also transporters, metabolic enzymes, and chaperones.

Topics: Acute Lung Injury; Anemia, Sickle Cell; Animals; Autoimmune Diseases; Cardiovascular Diseases; Cell Physiological Phenomena; Disease Models, Animal; Fingolimod Hydrochloride; Hematopoietic Stem Cell Mobilization; Humans; Influenza, Human; Lysophospholipids; Membrane Lipids; Mice; Multiple Sclerosis; Neoplasms; Neovascularization, Physiologic; Neurogenesis; Propylene Glycols; Receptors, Lysosphingolipid; Sphingolipids; Sphingosine

Apolipoprotein M (ApoM) is a novel apolipoprotein that was discovered in 1999 and is bound primarily to high-density lipoproteins (HDLs) in the plasma. Multiple factors may influence its expression at both the post-transcriptional and the transcriptional levels both in vivo and ex vivo as follows: hepatocyte nuclear factor-1α, 4α (HNF-1α, 4α), liver receptor homolog-1 (LRH-1), forkhead box A2 (Foxa2) and platelet activating factor (PAF) upregulate its expression; liver X receptor (LXR), retinoid X receptor (RXR), farnesoid X receptor (FXR), small heterodimer partner (SHP) and the majority of cytokines downregulate its expression. However, mechanisms underlying these processes remain unknown. Structurally, there exists a characterized hydrophobic binding pocket within the apoM protein, which enables it to bind functional lipids such as Sphingosine-1-Phosphate (S1P). Functionally, it facilitates the formation of preβ-HDL and enhances an avalanche of atheroprotective effects exerted by HDL. Moreover, in patients with diabetes, the levels of plasma apoM may decrease, whereas the augmentation of apoM decreases plasma glucose levels and magnifies the secretion of insulin. This article offers a panorama of the progress made in the research regarding the characteristics of apoM, particularly the regulation of its expression and its functions.

Topics: Animals; Apolipoproteins; Apolipoproteins M; Biomarkers; Cardiovascular Diseases; Hepatocyte Nuclear Factor 1-alpha; High-Density Lipoproteins, Pre-beta; Humans; Lipocalins; Lipoproteins, HDL; Lysophospholipids; Sphingosine

Sphingosine-1-phosphate (S1P) regulates important functions in cardiac and vascular homeostasis. It has been implied to play causal roles in the pathogenesis of many cardiovascular disorders such as coronary artery disease, atherosclerosis, myocardial infarction, and heart failure. The majority of S1P in plasma is associated with high-density lipoproteins (HDL), and their S1P content has been shown to be responsible, at least in part, for several of the beneficial effects of HDL on cardiovascular risk. The attractiveness of S1P-based drugs for potential cardiovascular applications is increasing in the wake of the clinical approval of FTY720, but answers to important questions on the effects of S1P in cardiovascular biology and medicine must still be found. This chapter focuses on the current understanding of the role of S1P and its receptors in cardiovascular physiology, pathology, and disease.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Drug Design; Hemodynamics; Humans; Lipoproteins, HDL; Lysophospholipids; Signal Transduction; Sphingosine

Bioactive sphingolipids are engaged with numerous cellular processes such as cell differentiation, proliferation and apoptosis. Sphingolipid metabolism in heart is regulated by physical exercise and PPARs. Ceramide, the main second messenger of sphingomyelin pathway of signal transduction, was found to be involved in development of cardiac dysfunction after ischemia/reperfusion. On the other hand ceramide derivative sphingosine- 1- phosphate has been shown to exert potent cardioprotective action and guards cardiomyocytes against ischemic/reperfusion injury. Pharmacological compounds, which regulate metabolism of sphingolipids can be potentially useful in treatment of selected cardiovascular diseases. The aim of this work is critical review of physiological and pathological role of sphingolipids in circulatory system.

Topics: Apoptosis; Cardiovascular Diseases; Ceramides; Humans; Lysophospholipids; Myocytes, Cardiac; Second Messenger Systems; Signal Transduction; Sphingolipids; Sphingosine

Sphingosine-1-phosphate (S1P) has been shown to exert potent cardioprotective action. It binds to the plasma membrane receptors. Three S1P receptors are present in the heart: 1, 2 and 3. Exogenous S1P increases viability of cardiomyocytes incubated under hypoxic conditions. It also reduces the infarct size in isolated, perfused rat heart after ischemia/reperfusion. Formation of S1P in the heart is catalyzed by the enzyme sphingosine kinase 1 and its catabolism by the enzyme sphingosine1-phosphate lyase. Reduction in the activity of sphingosine kinase 1 or knocking out its gene eliminates cardioprotective effect of ischemic preconditioning in mice. Knocking out the sphingosine-1-phosphate lyase gene exerts potent cardioprotective effect against ischemia/reperfusion in the mouse heart. The following mechanism of cardioprotection by S1P is suggested: S1P binds to its membrane receptors and the complex activates protein G. Activated protein G activates PI3K which in turn activates pro-survival Akt kinase. S1P activates also Stat3, a powerful cardioprotectant. It should be added that ischemia/reperfusion increases markedly the myocardial content of two other sphingolipids, namely sphingosine and ceramide. Sphingosine, a direct precursor of S1P, in a high dose is cardiotoxic. Ceramide (the key sphingolipid, a precursor of sphingosine) is claimed to be responsible for activation of apoptosis during ischemia/reperfusion. Therefore, the two latter sphingolipids may counteract, to a certain degree, the cardioprotective action of S1P. It is suggested, that development of specific S1P agonists and compounds modifying activity of the two enzymes could provide important therapeutic tools in the treatment of the heart infarct.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Humans; Lysophospholipids; Protein Binding; Receptors, Lysosphingolipid; Signal Transduction; Sphingolipids; Sphingosine

Sphingosine-1-phosphate (S1P) has gained special attention in the high-density lipoprotein (HDL) field because HDL is the most prominent plasma carrier of S1P and because the S1P content of HDL may be responsible for many of the pleiotropic functions of HDL. This revelation has come from the evidence that HDL employ S1P receptors and signalling pathways to implement several HDL-ascribed biological effects as diverse as endothelial nitric oxide production, vasodilation, survival, and cardioprotection. This review focuses on HDL effects that are completely or partially mediated by the S1P content of the HDL particle and differentiates them from genuine HDL effects that are S1P-independent. In addition, the functional properties of 'free', HDL-unbound S1P are sometimes different from or even contrary to those of HDL-associated S1P. The nature of the physical interactions between HDL and local and systemic S1P production will be discussed as well as their consequences for organ function. Finally, we will elucidate the potential benefits and limitations of S1P analogues as a new class of functional HDL mimetics for cardiovascular therapy.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Humans; Lipoproteins, HDL; Lysophospholipids; Neovascularization, Pathologic; Signal Transduction; Sphingosine; Vasoconstriction; Vasodilation

Lysophosphatidic acid (LPA), its sphingolipid homolog sphingosine 1-phosphate (S1P) and several other related molecules constitute a family of bioactive lipid phosphoric acids that function as receptor-active mediators with roles in cell growth, differentiation, inflammation, immunomodulation, apoptosis and development. LPA and S1P are present in physiologically relevant concentrations in the circulation. In isolated cell culture systems or animal models, these lipids exert a range of effects that suggest that S1P and LPA could play important roles in maintaining normal vascular homeostasis and in vascular injury responses. LPA and S1P act on a series of G protein-coupled receptors, and LPA may also be an endogenous regulator of PPARgamma activity. In this review, we discuss potential roles for lysolipid signaling in the vasculature and mechanisms by which these bioactive lipids could contribute to cardiovascular disease.

Topics: Blood Vessels; Cardiovascular Diseases; Homeostasis; Humans; Lysophospholipids; Sphingosine

One of the major lipid biology discoveries in last decade was the broad range of physiological activities of lysophospholipids that have been attributed to the actions of lysophospholipid receptors. The most well characterized lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Documented cellular effects of these lipid mediators include growth-factor-like effects on cells, such as proliferation, survival, migration, adhesion, and differentiation. The mechanisms for these actions are attributed to a growing family of 7-transmembrane, G protein-coupled receptors (GPCRs). Their pathophysiological actions include immune modulation, neuropathic pain modulation, platelet aggregation, wound healing, vasopressor activity, and angiogenesis. Here we provide a brief introduction to receptor-mediated lysophospholipid signaling and physiology, and then discuss potential therapeutic roles in human diseases.

Topics: Animals; Asthma; Autoimmune Diseases; Cardiovascular Diseases; Cell Adhesion; Cell Movement; Cell Proliferation; Cell Survival; Gap Junctions; Humans; Immunologic Factors; Lysophospholipids; Neoplasms; Receptors, G-Protein-Coupled; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

Increasing evidence suggests that High-density lipoproteins (HDL) are a direct cardioprotective agent in the setting of acute myocardial ischemia/reperfusion injury, and that this cardioprotection occurs independently of their atheroprotective effect. Studies on the involved mechanisms have revealed that the biologically active HDL-compound sphingosine-1-phosphate (S1P) is responsible for the beneficial effect of HDL on the myocardium. There appears to be an intricate interplay between known preconditioning agents and components of the S1P synthesis machinery in the heart, which makes S1P signalling an attractive downstream convergence point of preconditioning and cardioprotection at the level of its G protein-coupled receptors. While local S1P production has been known to protect the heart against ischemia/reperfusion injury and to mediate preconditioning, systemic S1P supply via HDL adds a novel aspect to the regulation of cardioprotection. Thus the S1P-content of HDL may serve both as a potential cardiovascular risk marker and a novel therapeutic target. Strategies for short-term "acute" HDL elevation as well as S1P analogues may prove beneficial not only in the high-risk patient but also in any patient at risk of myocardial ischemia.

Topics: Acute Disease; Cardiovascular Diseases; Creatine Kinase; Humans; Ischemic Preconditioning, Myocardial; Lipoproteins, HDL; Lysophospholipids; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Phosphotransferases (Alcohol Group Acceptor); Risk Factors; Signal Transduction; Sphingosine

This review summarizes data on the role of lysosphingolipids (glucosyl- and galactosylsphingosines, sphingosine-1-phosphate, sphingosine-1-phosphocholine) in the regulation of various biological processes in normal and pathological states.

Topics: Animals; Apoptosis; Cardiovascular Diseases; Cell Survival; Humans; Lysophospholipids; Psychosine; Skin Diseases; Sphingolipids; Sphingosine

The two lysophospholipids (LPs) lysophosphatidic acid and sphingosine 1-phosphate (S1P) regulate diverse biological processes. Over the past decade, it has become clear that medically relevant LP activities are mediated by specific G protein-coupled receptors, implicating them in the etiology of a growing number of disorders. A new class of LP agonists shows promise for drug therapy: the experimental drug FTY720 is phosphorylated in vivo to produce a potent S1P receptor agonist (FTY720-P) and is currently in Phase III clinical trials for kidney transplantation and Phase II for multiple sclerosis. Recent genetic and pharmacological studies on LP signaling in animal disease models have identified new areas in which interventions in LP signaling might provide novel therapeutic approaches for the treatment of human diseases.

Topics: Animals; Autoimmune Diseases; Cardiovascular Diseases; Humans; Lysophospholipids; Neoplasms; Obesity; Phosphorylation; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Transplantation Immunology

Sphingosine 1-phosphate (S1P), an evolutionarily conserved bioactive lipid mediator, is now recognized as a potent modulator of cell regulation. In vertebrates, S1P interacts with cell surface G protein-coupled receptors of the EDG family and induces profound effects in a variety of organ systems. Indeed, an S1P receptor agonist is undergoing clinical trials to combat immune-mediated transplant rejection. Recent information on S1P receptor biology suggests potential utility in the control of cardiovascular processes, including angiogenesis, vascular permeability, arteriogenesis, and vasospasm. However, studies from diverse invertebrates, such as yeast, Dictyostelium, Drosophila, and Caenorhabditis elegans have shown that S1P is involved in important regulatory functions in the apparent absence of EDG S1P receptor homologues. Metabolic pathways of S1P synthesis, degradation, and release have recently been described at the molecular level. Genetic and biochemical studies of these enzymes have illuminated the importance of S1P signaling systems both inside and outside of cells. The revelation of receptor-dependent pathways, as well as novel metabolic/intracellular pathways has provided new biological insights and may ultimately pave the way for the development of novel therapeutic approaches for cardiovascular diseases.

Topics: Aldehyde-Lyases; Animals; Cardiovascular Diseases; Cardiovascular System; Endothelium, Vascular; Fungi; Humans; Invertebrates; Lysophospholipids; Membrane Proteins; Muscle, Smooth, Vascular; Myocardium; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Plants; Receptors, G-Protein-Coupled; Receptors, Lysophospholipid; Second Messenger Systems; Species Specificity; Sphingosine; Vertebrates

[Figure: see text].

Topics: Adult; Animals; Biomarkers; Cardiovascular Diseases; Female; Humans; Hypertension; Inflammation; Logistic Models; Lysophospholipids; Male; Mice, Inbred C57BL; Middle Aged; Proteome; Proteomics; Sphingosine; Translational Research, Biomedical

Bone marrow-derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) were quantified using mass spectrometry. CPCs were assessed using flow cytometry. S1P levels correlated with the numbers of CD34+, CD34+/CD133+, and CD34+/CXCR4+ CPCs even after adjustment for potential confounding factors. However, no significant correlation was observed between C1P levels and CPC count. Plasma levels of S1P correlated with the number of CPCs in patients with coronary artery disease, suggesting an important mechanistic role for S1P in stem cell mobilization. The therapeutic effects of adjunctive S1P therapy to mobilize endogenous stem cells need to be investigated. Stem Cells Translational Medicine 2017;6:731-735.

Topics: Cardiovascular Diseases; Cell Count; Cell Movement; Female; Humans; Lipids; Lysophospholipids; Male; Middle Aged; Sphingosine; Stem Cells

Sphingolipids are bioactive molecules with a putative role in inflammation. Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin. Herein, we quantified the circulating sphingolipid profile in individuals with mild or severe psoriasis as well as healthy controls. In addition, the effects of anti-TNF-α treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P < 0.001; n = 32), but not in mild (n = 32), psoriasis relative to healthy controls (n = 32). These alterations were not reversed in severe patients (n = 16) after anti-TNF-α treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-α treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis.

Topics: Adult; Aged; Antibodies; Cardiovascular Diseases; Case-Control Studies; Ceramides; Chromatography, High Pressure Liquid; Fatty Acids; Female; Humans; Lysophospholipids; Male; Middle Aged; Psoriasis; RNA, Messenger; Severity of Illness Index; Skin; Sphingomyelins; Sphingosine; Sphingosine N-Acyltransferase; Tandem Mass Spectrometry; Tumor Necrosis Factor-alpha

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.

Topics: Animals; Area Under Curve; Cardiovascular Diseases; Chemistry, Physical; Drug Design; Female; Humans; Immunosuppressive Agents; In Vitro Techniques; Kinetics; Lymphocytes; Models, Chemical; Multiple Sclerosis; Quinolones; Rats; Rats, Inbred Lew; Receptors, Lysosphingolipid; Structure-Activity Relationship

Topics: Adipose Tissue; Amnion; Animals; Cardiovascular Diseases; Cell Movement; Endothelial Cells; Humans; Lysophospholipids; Mice; Microvessels; Neovascularization, Physiologic; Omentum; Receptors, Lysosphingolipid; Regeneration; Regenerative Medicine; Regional Blood Flow; rho GTP-Binding Proteins; rho-Associated Kinases; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Tissue Engineering; Tissue Scaffolds; Transplantation, Autologous

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (SIP) are potent bioactive lipids with specific and multiple effects on cells of the vessel wall and blood platelets. In this paper we suggest that these lipid molecules are involved in atherogenesis, pathological vasoconstriction, plaque rupture, and intravascular thrombus formation, which leads us to propose new strategies for the prevention and therapy of cardiovascular diseases. The conclusions are hypothetical, in that the studies were so far mainly carried out on isolated cells or cultured cells in vitro and the results were extrapolated to the situation in vivo.

Topics: Arteriosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Humans; Lysophospholipids; Phosphorylation; Signal Transduction; Sphingosine; Thrombosis