The role of sphingosine-1-phosphate receptors in the pathogenesis of Atherosclerosis

Sphingosin-1-Phosphat (S1P) ist ein biologisch aktives Sphingolipid, welches grund¬legende physiologische Prozesse wie Entzündung, Immunität und Angiogenese reguliert. Zunehmende Beachtung findet S1P neuerdings in der Herz-Kreislauf-Physiologie, wo es direkt oder als Bestandteil von High-Density Lipoproteinen (HDL) die Homöostase des Gefäßendothels, den Gefäßtonus und die kardiale Funktion beeinflusst. S1P vermittelt seine Signalwirkung über fünf G-Protein-gekoppelte Rezeptoren (S1P1-5), die auf kardiovaskulären und hämatopoetischen Zellen unterschiedliche Expressionsmuster zeigen. Im Plasma zirkuliert S1P als Bestandteil von HDL, wird lokal bei Entzündung freigesetzt, und entfaltet vielfältige biologische Wirkungen auf allen an der Atherosklerose beteiligten Zelltypen. Das macht eine kausale Beteiligung von S1P und seiner Rezeptoren an der Pathogenese der Atherosklerose sehr wahrscheinlich

Defects of High-Density Lipoproteins in Coronary Artery Disease Caused by Low Sphingosine-1-Phosphate Content Correction by Sphingosine-1-Phosphate—Loading

AbstractBackgroundSphingosine-1-phosphate (S1P) is a constituent of high-density lipoproteins (HDL) that contributes to their beneficial effects. We have shown decreased HDL-S1P in coronary artery disease (CAD) but its functional relevance remains unclear.ObjectivesThis study investigated the functional consequences of reduced HDL-S1P content in CAD and tested if increasing it may improve or restore HDL function.MethodsHuman HDL from healthy and CAD subjects, as well as mouse HDL, were isolated by ultracentrifugation. HDL-S1P-dependent activation of cell-signaling pathways and induction of vasodilation were examined in vitro and in isolated arteries using native and S1P-loaded HDL, S1P receptor antagonists, and S1P-blocking antibodies.ResultsHDL-S1P-dependent signaling was clearly impaired and S1P content reduced in CAD-HDL as compared to healthy HDL. Both healthy and CAD-HDL could be efficiently and equally well loaded with S1P from cellular donors and plasma. S1P-loading greatly improved HDL signaling and vasodilatory potential in pre-contracted arteries and completely corrected the defects inherent to CAD-HDL. HDL-S1P content and uptake was reduced by oxidation and was lower in HDL3 than HDL2. Loading with S1P in vitro and in vivo fully replenished the virtually absent S1P content of apolipoprotein M-deficient HDL and restored their defective signaling. Infusion of erythrocyte-associated C17-S1P in mice led to its rapid and complete uptake by HDL providing a means to directly S1P-load HDL in vivo.ConclusionsReduced HDL-S1P content contributes to HDL dysfunction in CAD. It can be efficiently increased by S1P-loading in vitro and in vivo, providing a novel approach to correcting HDL dysfunction in CAD

Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin

Sphingosine-1-phosphate (S1P) participates in inflammation;however, its role in leukocyte rolling is still unclear. Here we use intravital microscopy in inflamed mouse cremaster muscle venules and human endothelial cells to show that S1P contributes to P-selectin-dependent leukocyte rolling through endothelial S1P receptor 3 (S1P(3)) and G alpha(q), PLC beta and Ca2+. Intraarterial S1P administration increases leukocyte rolling, while S1P(3) deficiency or inhibition dramatically reduces it. Mast cells involved in triggering rolling also release S1P that mobilizes P-selectin through S1P(3). Histamine and epinephrine require S1P(3) for full-scale effect accomplishing it by stimulating sphingosine kinase 1 (Sphk1). In a counter-regulatory manner, S1P1 inhibits cAMP-stimulated Sphk1 and blocks rolling as observed in endothelial-specific S1P(1)(-/-) mice. In agreement with a dominant pro-rolling effect of S1P(3),FTY720 inhibits rolling in control and S1P(1)(-/-) but not in S1P(3)(-/-) mice. Our findings identify S1P as a direct and indirect contributor to leukocyte rolling and characterize the receptors mediating its action

Assimilation of Particular Organic Matter and Dissolved Organic or Inorganic Compounds by Cribroelphidium selseyense (Foraminifera)

Marine carbon and nitrogen processing through microorganisms’ metabolism is an important aspect of the global element cycles. For that purpose, we used foraminifera to analyze the element turnover with different algae food sources. In the Baltic Sea, benthic foraminifera are quite common and therefore it is important to understand their metabolism. Especially, Cribroelphidium selseyense, also occurring in the Baltic Sea, has often been used for laboratory feeding experiments to test their effect on carbon or nitrogen turnover. Therefore, foraminifera were collected from the Kiel Fjord and fed with six different algal species in two qualities (freeze-dried algae vs. fresh algae, all 13C- and 15N-labeled). Also, labeled dissolved inorganic C and N compounds and glucose were offered to the foraminifera to test direct assimilation of dissolved compounds (carbon and nitrogen) from the water column. Our experiments showed that after 15 days of incubation, there were highly significant differences in isotope labeling in foraminifera fed with fresh algae and dry algae, depending on algal species. Further, different algal species led to different 13C and 15N enrichment in the studied foraminifera, highlighting a feeding preference for one diatom species and an Eustigmatophyte. A significant carbon assimilation from HCO3– was observed after 7 days of incubation. The N assimilation from NH4+ was significantly higher than for NO3– as an inorganic N source. The uptake of glucose showed a lag phase, which was often observed during past experiments, where foraminifera were in a steady state and showed no food uptake at regular intervals. These results highlight the importance of food quality on the feeding behavior and metabolic pathways for further studies of foraminiferal nutrition and nutrient cycling

ВЛИЯНИЕ ГРАНУЛОМЕТРИЧЕСКОГО СОСТАВА МАТЕРИАЛА НА ЭФФЕКТИВНОСТЬ БЕСШАРОВОГО ИЗМЕЛЬЧЕНИЯ

Процес грохочення моделюється марковським ланцюгом. Тривалість грохочення визна-чена для випадку, коли просівання домінує над сегрегацією. Використано апарат матричної алгебри.Процес грохочення моделюється марковським ланцюгом. Тривалість грохочення визна-чена для випадку, коли просівання домінує над сегрегацією. Використано апарат матричної алгебри