prostaglandin-d2 and Thrombosis

The actions of prostanoids in various physiological and pathophysiological conditions have been examined using mice lacking the prostanoid receptors. PGD2 was found to be a mediator of allergic asthma. Prostaglandin (PG) I2 worked not only as a mediator of inflammation but also as an antithrombotic and cardio-protective agent. Several important actions of PGE2 are brought out via the PGE2-receptor subtype EP3; PGE2 participated in the regulation of platelet function, and it worked as a mediator of febrile responses to both endogenous and exogenous pyrogens. These novel findings on the roles of the prostanoids would contribute to the development of drugs targeting the prostanoid receptors.

Topics: Animals; Asthma; Dinoprostone; Drug Design; Epoprostenol; Fever; Humans; Inflammation Mediators; Myocardial Reperfusion Injury; Platelet Activation; Prostaglandin D2; Prostaglandins; Receptors, Prostaglandin; Thrombosis

The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD(2) on platelet function, i.e. platelet aggregation, Ca(2+) flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca(2+) flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease.

Topics: Blood Coagulation; Blood Platelets; Calcium; Dyslipidemias; Female; Gene Expression Regulation; Humans; Hypolipidemic Agents; Indoles; Male; Niacin; P-Selectin; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Prostaglandin D2; Receptors, Prostaglandin E, EP3 Subtype; Thrombosis

Peroxisome proliferator-activated receptor-(gamma) (PPAR(gamma)) is expressed in human platelets although in the absence of genomic regulation in these cells, its functions are unclear.. In the present study, we aimed to demonstrate the ability of PPAR(gamma) ligands to modulate collagen-stimulated platelet function and suppress activation of the glycoprotein VI (GPVI) signaling pathway.. Washed platelets were stimulated with PPAR(gamma) ligands in the presence and absence of PPAR(gamma) antagonist GW9662 and collagen-induced aggregation was measured using optical aggregometry. Calcium levels were measured by spectrofluorimetry in Fura-2AM-loaded platelets and tyrosine phosphorylation levels of receptor-proximal components of the GPVI signaling pathway were measured using immunoblot analysis. The role of PPAR(gamma) agonists in thrombus formation was assessed using an in vitro model of thrombus formation under arterial flow conditions.. PPAR(gamma) ligands inhibited collagen-stimulated platelet aggregation that was accompanied by a reduction in intracellular calcium mobilization and P-selectin exposure. PPAR(gamma) ligands inhibited thrombus formation under arterial flow conditions. The incorporation of GW9662 reversed the inhibitory actions of PPAR(gamma) agonists, implicating PPAR(gamma) in the effects observed. Furthermore, PPAR(gamma) ligands were found to inhibit tyrosine phosphorylation levels of multiple components of the GPVI signaling pathway. PPAR(gamma) was found to associate with Syk and LAT after platelet activation. This association was prevented by PPAR(gamma) agonists, indicating a potential mechanism for PPAR(gamma) function in collagen-stimulated platelet activation.. PPAR(gamma) agonists inhibit the activation of collagen-stimulation of platelet function through modulation of early GPVI signalling.

Topics: Adaptor Proteins, Signal Transducing; Anilides; Animals; Blood Platelets; Calcium; Collagen; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins; Ligands; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; P-Selectin; Phosphorylation; Platelet Aggregation; Platelet Endothelial Cell Adhesion Molecule-1; Platelet Membrane Glycoproteins; PPAR gamma; Prostaglandin D2; Protein-Tyrosine Kinases; Rosiglitazone; Signal Transduction; Spectrometry, Fluorescence; Syk Kinase; Thiazolidinediones; Thrombosis; Time Factors; Tyrosine

The 15-deoxyDelta prostaglandin J2 (15-dPGJ2) is an anti-inflammatory prostaglandin that has been proposed to be the endogenous ligand of peroxisome proliferator-activated receptor-gamma (PPARgamma), a nuclear receptor that can exert potent anti-inflammatory actions by repressing inflammatory genes when activated. It has been suggested that 15-dPGJ2 could be beneficial in neurological disorders in which inflammation contributes to cell death such as stroke.. We investigated the relationship between plasma levels of 15-dPGJ2 and early neurological deterioration (END), infarct volume, and neurologic outcome in 552 patients with an acute stroke admitted within 24 hours after symptoms onset.. Median [quartiles] plasma 15-dPGJ2 levels on admission were significantly higher in patients than in controls (60.5 [11.2 to 109.4] versus 5.0 [3.8 to 7.2] pg/mL; P<0.0001). Levels of this prostaglandin were also significantly higher in patients with vascular risk factors (history of hypertension or diabetes) and with atherothrombotic infarcts (113.9 [81.6 to 139.7] pg/mL), than in those with lacunar (58.7 [32.7 to 86.2] pg/mL), cardioembolic (12.1 [6.5 to 39.2] pg/mL), or undetermined origin infarcts (11.4 [5.6 to 24.3] pg/mL) (P<0.0001). In the subgroup of patients with atherothrombotic infarcts, the adjusted odds ratio of END and poor outcome for 1 pg/mL increase in 15-dPGJ2 were 0.95 (95% CI, 0.94 to 0.97) and 0.97 (95% CI, 0.96 to 0.98), respectively. In a generalized linear model, by 1 U increase in 15-dPGJ2, there was a reduction of 0.47 mL (95% CI, 0.32 to 0.63) in the mean estimated infarct volume.. Increased plasma 15-dPGJ2 concentration is associated with good early and late neurological outcome and smaller infarct volume. These findings suggest a neuroprotective effect of 15-dPGJ2 in atherothrombotic ischemic stroke.

Topics: Acute Disease; Aged; Anti-Inflammatory Agents; Brain Ischemia; Case-Control Studies; Female; Humans; Inflammation; Ligands; Male; Middle Aged; Nervous System Diseases; Odds Ratio; PPAR gamma; Prostaglandin D2; Regression Analysis; Stroke; Thrombosis; Time Factors; Treatment Outcome