Home About us Contact
|
Home About us Contact | ||
|
|
||
Platelet Shape Change (platelet + shape_change)
Selected AbstractsThrombogenic and atherogenic activities of lysophosphatidic acidJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2004Wolfgang Siess Abstract Lysophosphatidic acid (LPA) has been identified as a biologically active lipid in mildly-oxidized LDL, human atherosclerotic lesions, and the supernatant of activated platelets. The evidence that LPA has thrombogenic and atherogenic activities has increased substantially in recent years. Supporting the thrombogenic activity of LPA, analysis of the core region of human carotid plaques revealed recently the presence of alkyl- and acyl-molecular species from LPA with high platelet-activating potency (16:0 alkyl-LPA, 20:4 acyl-LPA). LPA, lipid extracts of atherosclerotic plaques, and the lipid-rich core elicited shape change and, in synergy with other platelet stimuli, aggregation of isolated platelets. This effect was completely abrogated by prior incubation of platelets with LPA receptor antagonists. Furthermore, LPA at concentrations approaching those found in vivo, induced platelet shape change, aggregation, and platelet-monocyte aggregate formation in blood. LPA-stimulated platelet aggregation was mediated by the ADP-stimulated activation of the P2Y1 and P2Y12 receptors. Supporting its atherogenic activity, LPA is a mitogen and motogen to vascular smooth muscle cells (VSMCs) and an activator of endothelial cells and macrophages. Recently, LPA has been identified as an agonist of the peroxisome proliferator activating receptor , (PPAR,), which is a key regulator of atherogenesis. LPA elicits progressive neointima formation, which is fully abolished by GW9662, an antagonist of PPAR,. We propose that LPA plays a central role in eliciting vascular remodeling and atherogenesis. Furthermore, upon rupture of lipid-rich atherosclerotic plaques, LPA may trigger platelet aggregation and intra-arterial thrombus formation. Antagonists of LPA receptors might be useful in preventing LPA-elicited thrombus formation and neointima formation in patients with cardiovascular diseases. © 2004 Wiley-Liss, Inc. [source] (N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2006D. M. BOURDON Summary., Adenosine diphosphate (ADP) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq -coupled P2Y1 receptor and the Gi -coupled P2Y12 receptor. We recently described the synthesis and P2Y1 receptor-specific agonist activity of (N)-methanocarba-2MeSADP (MRS2365). Consequences of selective activation of the P2Y1 receptor by MRS2365 have been further examined in human platelets. Whereas MRS2365 alone only induced shape change, addition of MRS2365 following epinephrine treatment, which activates the Gi/z -linked, ,2A -adrenergic receptor, resulted in sustained aggregation that was indistinguishable from that observed with ADP. Conversely, the platelet shape change promoted by ADP in the presence of the GPIIb/IIIa antagonist eptifibatide was similar to that promoted by MRS2365. Preaddition of the high affinity P2Y1 receptor antagonist MRS2500 inhibited the effect of MRS2365, whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365-induced shape change. Preactivation of the P2Y1 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20-fold rightward shift in the concentration effect curve of ADP. This inhibitory effect of P2Y1 receptor activation was dependent on the concentration of MRS2365 (EC50 = 34 nm). The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq -coupled 5-HT2A receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq -coupled P2Y1 receptor. The time course of MRS2365-induced loss of aggregation response to epinephrine was similar to that observed with ADP. These results further demonstrate the P2Y1 receptor selectivity of MRS2365 and illustrate the occurrence of agonist-induced desensitization of the P2Y1 receptor of human platelets studied in the absence of P2Y12 receptor activation . [source] Further evidence that fibrillar collagen is unable to promote platelet shape change and aggregation in the absence of secondary agonistsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2005P. OHLMANN [source] The P2Y1 receptor plays an essential role in the platelet shape change induced by collagen when TxA2 formation is preventedJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2004P. Mangin Summary., ADP and TxA2 are secondary agonists which play an important role as cofactors when platelets are activated by agonists such as collagen or thrombin. The aim of the present study was to characterize the role of the ADP receptor P2Y1 in collagen-induced activation of washed platelets. Inhibition of P2Y1 alone with the selective antagonist MRS2179 prolonged the lag phase preceding aggregation in response to low or high concentrations of fibrillar collagen, without affecting the maximum amplitude of aggregation or secretion. A combination of MRS2179 and aspirin resulted in complete inhibition of platelet shape change at low and high collagen concentrations, together with a profound decrease in aggregation and secretion. Scanning electron microscopy showed that these platelets had conserved the discoid morphology typical of the resting state. A lack of shape change was also observed in aspirin-treated P2Y1 - and G,q -deficient mouse platelets and in ,-storage pool-deficient platelets from Fawn Hooded rats. In contrast, when the second ADP receptor P2Y12 was inhibited with AR-C69931MX, aspirin-treated platelets were still able to change shape and displayed only a moderate decrease in aggregation and secretion. In conclusion, this study provides evidence that collagen requires not only the TxA2 receptor Tp,, but also P2Y1, to induce platelet shape change. [source] Biological properties of a specific G,q/11 inhibitor, YM-254890, on platelet functions and thrombus formation under high-shear stressBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006Toshio Uemura 1The effects of YM-254890, a specific G,q/11 inhibitor, on platelet functions, thrombus formation under high-shear rate condition and femoral artery thrombosis in cynomolgus monkeys were investigated. 2YM-254890 concentration dependently inhibited ADP-induced intracellular Ca2+ elevation, with an IC50 value of 0.92±0.28 ,M. 3P-selectin expression induced by ADP or thrombin receptor agonist peptide (TRAP) was strongly inhibited by YM-254890, with IC50 values of 0.51±0.02 and 0.16±0.08 ,M, respectively. 4YM-254890 had no effect on the binding of fibrinogen to purified GPIIb/IIIa, but strongly inhibited binding to TRAP-stimulated washed platelets. 5YM-254890 completely inhibited platelet shape change induced by ADP, but not that induced by collagen, TRAP, arachidonic acid, U46619 or A23187. 6YM-254890 attenuated ADP-, collagen-, TRAP-, arachidonic acid- and U46619-induced platelet aggregation with IC50 values of <1 ,M, whereas it had no effect on phorbol 12-myristate 13-acetate-, ristocetin-, thapsigargin- or A23187-induced platelet aggregation. 7High-shear stress-induced platelet aggregation and platelet-rich thrombus formation on a collagen surface under high-shear flow conditions were concentration dependently inhibited by YM-254890. 8The antithrombotic effect of YM-254890 was evaluated in a model of cyclic flow reductions in the femoral artery of cynomolgus monkeys. The intravenous bolus injection of YM-254890 dose dependently inhibited recurrent thrombosis without affecting systemic blood pressure or prolonging template bleeding time. 9YM-254890 is a useful tool for investigating G,q/11 -coupled receptor signaling and the physiological roles of G,q/11. British Journal of Pharmacology (2006) 148, 61,69. doi:10.1038/sj.bjp.0706711 [source] | ||||||||||