P selectin

The recruitment of blood-borne cells to evolving atherosclerotic lesions appears to be specific for monocytes and requires the inducement of specific adhesion molecules on both the endothelial cell surface and the recruited monocytes. The adhesion process appears to be a multistep phenomenon. In the initial stages E- or P-selectin expressed by stimulated endothelial cells binds to carbohydrates borne by surface molecules on monocytes. Expression of P-selectin on vascular endothelial cells slows white blood cells and causes them to roll along the endothelial surface. Other cell adhesion molecules, including ICAM-1 and vascular cell adhesion molecule 1, then latch onto and stop the white blood cells completely, prior to their migration out of the blood vessel and into the target tissue. 

Endothelial cells located in the vicinity of atherosclerotic lesions, although morphologically intact in the early stages of atherosclerosis, present a number of abnormalities in that they exhibit decreased basal production of NO as well as an impaired responsiveness to endothelium-dependent vasodilators (Drexler et al., 1989). For example, serotonin, which dilates normal human coronary arteries, causes a paradoxical vasoconstriction in 

FIGURE 4 Densitometric analysis of Northern blots showing the effects of nitric oxide (NO) on the expression of monocyte chemoattractant protein (MCP-1) mRNA. Cultured human umbilical vein endothelial cells were incubated for 12 hr with solvent (control), the NO synthase inhibitor N°-nitro-L-arginine (L-NAG), or the NO donor SIN-1. Data were obtained using five different cell preparations. P 0.01. 

Synetos et al., 1993). These findings provide further evidence that NO may be involved in the maintenance of the nonangiogenic status of the vascular endothelium. 

There are most likely a number of diverse molecular pathways by which NO can alter gene expression, but in the case of MCP-1 this pathway has been partially elucidated. In human endothelial cells inhibition of NO synthesis has been shown to activate proteins capable of binding to oligonucleotides containing the NF-kB binding site (Zeiher etal., 1995), suggesting a molecular link between an oxidant-sensitive transcriptional regulatory mechanism and NO synthesis. However, it cannot be excluded that NO also influences the activation of other transcription factors, such as AP-1, which has recently been characterized as an antioxidant-responsive factor (Meyer et al., 1993). Indeed, in in vitro gel-mobility assays the NO donor sodium nitroprusside, but no free NO, has been reported to S-nitrosylate the AP-1 moiety and inhibit its activity (Tabuchi et al., 1994). 

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P-selectin, VEGFR2, VCAM, pPAR, CD55, Eotaxin-3, MCP-1... 

P-selectin EC, platelets P-selectin glycoprotein ligand-1 (PSGL-1) Sialyl-Lewis" and others... 

PPD Purified protein derivative PPME Polymeric polysaccharide rich in mannose-6-phosphate moieties PRA Percentage reactive activity PRD, PRDII Positive regulatory domain, -II PR3 Proteinase-3 PRBC Parasitized red blood cell proET-1 Proendothelin-1 PRL Prolactin PRP Platelet-rich plasma PS Phosphatidylserine P-selectin Platelet selectin formerly known as platelet adctivation-dependent granule external membrane protein (PADGEM), granule membrane protein of MW 140 kD (GMP-140)... 

Fig. 1. Surface phenotype of HSPCs. Primitive HSPCs have the phenotype of c-KitThy-ll0WLin CD34+CD33 in humans, and the mouse counterparts have the phenotype of c-KifThy-llowLin Sca-l+. Primitive HSPCs express CXCR4 as the major chemokine receptor and various adhesion molecules such as VLA-4, VLA-5, LFA-1, P-selectin glycoprotein ligand-1 (PSGL-1), and CD44 for migration to the stem cell niche.

Fig. 4. The role of RANTES in recruiting monocytes and T lymphocytes to injured endothelium involves the binding of platelets to activated endothelium in a P-selectin-dependent manner with subsequent secretion of RANTES by bound platelets. RANTES can then attract CCR5-expressing monocytes and T cells to the damaged endothelium as well as causing monocyte firm adhesion to occur via binding to platelet-derived RANTES deposited on the endothelial cell layer.

Schober A, Manka D, von HP, et al. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation 2002 106(12) 1523-1529. 

CD62P or P-selectin, which is a component of the platelet a granule membrane of resting platelets. It is expressed on the platelet surface membrane only after a granule secretion. P-selectin mediates the adhesion of activated platelets to neutrophils and monocytes. 

Of the four markers just mentioned, the expression of P-selectin on the activated platelets is the most widely studied. However, CD62P may not be the ideal marker for detection of circulating degranulated platelets, because they may rapidly lose their surface P-selectin but yet may continue to function. The decrease in the platelet surface expression of the GPIb-IX-V complex (CD42) perhaps represents a more sensitive marker of in vivo platelet activation. Apparently platelet activation related to strenuous exercise is more readily detected using CD42 than other markers (99). 

The CTAD additive mixture has found application in the monitoring of heparin therapy by either the chromogenic substrate assay or the APTT and in the measurement of platelet markers such as P-selectin (CD62) by flow cytometry (108, 109). 

Nemmar, A. et al. (2007) Enhanced peripheral fhrombogenidty after lung inflammation is mediated by platelet-leukocyte activation role of P-selectin. Journal of Thrombosis and Haemostasis,... 

Garcfa-Martfnez MC, Labios M, Hermenegildo C, Tarfn JJ, O Connor E, Cano A (2004) The effect of hormone replacement therapy on Ca2+ mobilization and P-selectin (CD62P) expression in platelets examined under flow cytometry. Blood Coagul Fibrinolysis 15 1-8... 

A Compound P-selectin (IC50 mM) L-selectin (IC50 mM) E-selectin (IC50 mM)... 

SIN-1 spontaneously releases NO and superoxide under physiological conditions thereby stimulating cGMP production. SIN-1 significantly decreased expression of P-selectin and both total and activated GP Ilb/IIIa and also promoted reversal of activated GP Ilb/IIIa complex in platelets stimulated with thrombin [61]. However, in rats SIN-1 could only partially reduce the degree of platelet activation [62]. SIN-1 stimulated VASP Ser157 phosphorylation and inhibited GP Ilb/IIIa activation. Threshold... 

SNAC is the most potent inhibitor of collagen-induced platelet aggregation in vitro compared to other S-nitrosothiols (SNAP, GSNO, CysNO and HomocysNo). Although it increased cGMP-levels in platelets [47], SNAC only partially inhibited thrombin-induced P-selectin expression on a platelet surface [79]. 

Parallel synthesis of 62 different fucosylated tripeptides resulted in two ligands with submicromolar affinity for the P-selectin however, the desired activity for the E-selectin was not observed.98 For the E-selectin selectivity, it was necessary to incorporate a hydroxyl group that mimics the 4-hydroxyl of the central Gal in SLex in addition to a Fuc-residue and a carboxylate to obtain ligands with > 10-fold increased activity over that of the SLex tetrasaccharide.81 One of the best ligands was obtained from Thr(a-Fuc)-OEt, which was first /V-acylated with a hydroxyl amino acid and then elongated with a di-acid to furnish the acid mimic of the sialic acid carboxylate (Fig. 14.4). This approach was further developed as a solid-phase method where the molecule was linked to a solid support through the invariable fucosyl moiety.99... 

On the neutrophil, the major selectin expressed is L-selectin. This molecule is constitutively expressed on mature neutrophils but may be expressed at low levels (50% of adult) in neonates. Stimulation of endothelial cells with thrombin, histamine, IL-1 and some other agents induces neutrophils (and other leukocytes) to leave the circulation and adhere to the endothelium. They do this by rolling onto the surface of the endothelium, to which they attach via P-selectin translocated from storage sites in Weibel-Palade bodies to the surface of the endothelium upon activation. The expression of P-selectin is short-lived and is replaced on the endothelial surface by E-selectin (whose expression is also regulated by some cytokines), which continues the endothelial-leukocyte interaction. 

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