Lipid phosphate phosphatase 3 in endothelial and epithelial cells promotes efficient T cell emigration from the thymus to the periphery.
Rationale The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) and thereby terminates their signaling effects. While emerging evidence links LPA to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. Objective The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses. Methods and Results We report that LPP3 is expressed in vascular SMC following experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation, (ERK) activity, Rho activation, and migration in response to serum and LPA. These effects are at least partially a consequence of LPP3-catalyzed LPA hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury. Conclusions Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk.
Anaemia and RBC (red blood cell) transfusion may be associated with worse clinical outcomes, especially with longer blood storage duration prior to transfusion. The mechanisms underlying these harmful effects are unknown. RBCs have been proposed to buffer plasma S1P (sphingosine 1-phosphate), a lysophospholipid essential for the maintenance of endothelial integrity and important in the regulation of haematopoietic cell trafficking. The present study examined the effect of anaemia, RBC transfusion and RBC storage duration on plasma S1P levels. Plasma S1P from 30 individuals demonstrated a linear correlation with Hct (haematocrit; R2=0.51, P<0.001) with no evidence for a plateau at Hct values as low as 19%. RBC transfusion in 23 anaemic patients with baseline mean Hct of 22.2±0.34% (value is the mean±S.D.) increased Hct to 28.3±0.6% at 72 h. Despite an Hct increase, RBC transfusion failed to elevate plasma S1P consistently. A trend towards an inverse correlation was observed between RBC storage duration and the post-transfusion increase in plasma S1P. After 30 days of storage, RBC S1P decreased to 19% of that observed in fresh (3–7-day-old) RBC segments. RBC membranes contain low levels of both S1P phosphatase and S1P lyase activities that may account for the decline in S1P levels with storage. Our results support a role for RBCs in buffering plasma S1P and identify a disturbance in the capacity after transfusion. Changes in S1P content may contribute to an RBC storage lesion. Further studies should investigate the clinical significance of alterations in circulating S1P levels and the potential value of enriching stored RBCs with S1P.
The N-methyl-D-aspartate receptor is an important mediator of the behavioral effects of ethanol in the central nervous system. Previous studies have demonstrated sites in the third and fourth membrane-associated (M) domains of the N-methyl-Daspartate receptor NR2A subunit that influence alcohol sensitivity and ion channel gating. We investigated whether two of these sites, Phe-637 in M3 and Met-823 in M4, interactively regulate the ethanol sensitivity of the receptor by testing dual substitution mutants at these positions. Ethanol is unusual among the major drugs of abuse in that it acts only at high concentrations (in the millimolar range) and that it acts on multiple targets in the central nervous system. For the greater part of the last century, ethanol was generally believed to produce its effects on central nervous system function via nonspecific actions on neuronal lipids, but it is now well accepted that the biologically important actions of ethanol are due to its interactions with proteins (1, 2). Of these proteins, the N-methyl-D-aspartate (NMDA) 2 receptor is among the most important target sites of ethanol in the central nervous system. At relevant concentrations, ethanol inhibits ionic current (3), synaptic potentials (4), Ca 2ϩ influx (5, 6), and neurotransmitter release (7) mediated by NMDA receptors. Studies of the mechanism of this inhibition have shown that it does not involve competitive inhibition at the glutamate or glycine binding sites (7-12) or interaction with sites for other allosteric modulators (8,12) or open channel block (13,14) but that it involves changes in NMDA receptor gating, notably mean open time and opening frequency (13,14). Thus, ethanol appears to inhibit NMDA receptors via low affinity interactions with sites that regulate ion channel gating. Although sites in the intracellular C-terminal domain may modulate both ethanol sensitivity of the NMDA receptor (15) and ion channel gating (16 -19), this domain does not contain the site of ethanol action, since removal of this region of the protein does not decrease ethanol inhibition of the receptor (20).In a previous study, Ronald et al. (21) demonstrated that a phenylalanine residue (Phe-639) in the third membrane-associated (M) domain of the NMDA receptor NR1 subunit influences alcohol sensitivity and shows some characteristics of a site of alcohol action. A previous study from this laboratory (22) identified a methionine residue in the M4 domain of the NMDA receptor NR2A subunit that also influences alcohol sensitivity and that fulfills some of the criteria for a site of alcohol action. The methionine in M4, however, also profoundly affects the gating behavior of the ion channel (23). We have recently shown (24) that the cognate position of NR1(Phe-639) in the NR2A subunit, Phe-637, also regulates alcohol sensitivity as well as desensitization and agonist potency. Studies in ␥-aminobutyric acid A and glycine receptors have demonstrated residues in transmembrane domains 2 and 3 that form sites of alcohol and anesthetic act...
Abbreviations used: CD4SP, CD4 single-positive; DN, double negative; DP, double positive; LPP3, lipid phosphate phosphatase 3; MFI, mean fluorescence intensity; pIpC, polyinosinic:polycytidylic acid; S1P, sphingosine-1-phosphate; S1PR1, S1P receptor 1; SPP1, S1P phosphatase 1.
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