sphingosine-1-phosphate and Hypercholesterolemia

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

Topics: Animals; Apolipoproteins E; Cell Movement; Chemokine CCL21; Hypercholesterolemia; Hypertrophy; Lymph Nodes; Lymphatic Vessels; Lymphocytes; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Sphingosine

Population-wide reductions in cardiovascular disease (CVD) have not been equally shared in the African American community due to a higher burden of CVD risk factors such as metabolic disorders and obesity. Differential concentrations of sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P) has been associated with the development of CVD, metabolic disorders (MetD), and obesity. Whether African Americans have disparate expression levels of sphingolipids that explain higher burdens of CVD remains unknown.. A cross sectional analysis of plasma concentrations of ceramides, sphingosine, and S1P were measured from 8 whites and 7 African Americans without metabolic disorders and 7 whites and 8 African Americans with metabolic disorders using high performance liquid chromatography/tandem mass spectrometry methodology (HPLC/MS-MS). Subjects were stratified by both race and metabolic status. Subjects with one or more of the following physician confirmed diagnosis: diabetes, hypertension, hypercholesterolemia, or dyslipidemia were classified as having metabolic disease (MetD). Data was analyzed using a Two-Way ANOVA and Tukey's post hoc test.. Total ceramide levels were increased in African Americans compared to African Americans with MetD. Ceramide C16 levels were higher in whites with MetD compared to African Americans with MetD (p<0.05). Ceramide C20 levels were higher in whites with MetD compared to whites. Ceramide C20 levels were higher in African Americans compared to African Americans with MetD. Furthermore, whites with MetD had higher levels of C20 compared to African Americans with MetD (p<0.0001). Ceramide C24:0 and C24:1 in African Americans was higher compared to African Americans with MetD (p<0.05). The plasma concentration of Sph-1P ceramide was higher in African Americans vs whites (p = 0.01). Lastly, ceramide C20 negatively correlated with hemoglobin A1c (HbA1c) levels in our study cohort.. Plasma ceramide concentration patterns are distinct in African Americans with MetD. Further research with larger samples sizes are needed to confirm these findings and to understand whether racial disparities in sphingolipid concentrations have potential therapeutic implications for CVD-related health outcomes.

Topics: Adult; Aged; Black or African American; Ceramides; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Diabetes Mellitus; Dyslipidemias; Female; Gas Chromatography-Mass Spectrometry; Humans; Hypercholesterolemia; Hypertension; Lysophospholipids; Male; Middle Aged; Risk Factors; Sphingosine; White People

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

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

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