Long Term Aspirin in the Prevention of Cardiovascular Disorders

Catella-Lawson, Francesca; FitzGerald, Garret A.

doi:10.2165/00002018-199513020-00001

Cited by 10 publications

(5 citation statements)

References 45 publications

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“…The use of aspirin as an antithrombotic drug substantiates the role of thromboxane A 2 generation under pathophysiological conditions. 33 Under normal physiological conditions, however, thromboxane A 2 generation might be blocked by calcium ions, which is probably a regulatory mechanism to prevent unwanted generation of positive feedback regulators.…”

Section: Effect Of Outside-in Signaling On Thromboxane a 2 Generationmentioning

confidence: 99%

Adenosine diphosphate (ADP)–induced thromboxane A2generation in human platelets requires coordinated signaling through integrin αIIbβ3 and ADP receptors

Jin

Quinton

Zhang

et al. 2002

Blood

152

114

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Adenosine diphosphate (ADP) is a platelet agonist that causes platelet shape change and aggregation as well as generation of thromboxane A 2 , another platelet agonist, through its effects on P2Y1, P2Y12, and P2X1 receptors. It is now reported that both 2-propylthio-D-␤␥-dichloromethylene adenosine 5-triphosphate (AR-C67085), a P2Y12 receptor-selective antagonist, and adenosine-2-phosphate-5-phosphate (A2P5P), a P2Y1 receptor-selective antagonist, inhibited ADP-induced thromboxane A 2 generation in a concentration-dependent manner, indicating that coactivation of the P2Y12 and P2Y1 receptors is essential for this event. SC49992, a fibrinogen receptor antagonist, blocked ADP-induced platelet aggregation and thromboxane A 2 production in a concentration-dependent manner. Similarly, P2 receptor antagonists or SC49992 blocked ADP-induced arachidonic acid liberation. Whereas SC49992 blocked arachidonic acid-induced platelet aggregation, it failed to inhibit thromboxane A 2 generation induced by arachidonic acid. Thus, ADPinduced arachidonic acid liberation, but not subsequent conversion to thromboxane A 2 , requires outside-in signaling through the fibrinogen receptor. The Fab fragment of ligand-induced binding site-6 (LIBS6) antibody, which induces a fibrinogen-binding site on the integrin ␣ IIb ␤ 3 , caused both platelet aggregation and thromboxane A 2 generation. Inhibitors of phosphoinositide 3-kinase, Syk, Src kinases, or protein tyrosine phosphatases inhibited platelet aggregation but not thromboxane A 2 generation, indicating that these signaling molecules have no significant role in phospholipase A 2 activation. In the presence of P2 receptor antagonists A2P5P or AR-C67085, LIBS6 failed to generate thromboxane A 2 , suggesting that inside-out signaling through ADP receptors is necessary for this event. It was concluded that both outside-in signaling from the fibrinogen receptor and inside-out signaling from the P2Y1 and P2Y12 receptors are necessary for phospholipase A 2 activation, resulting in arachidonic acid liberation and thromboxane IntroductionAdenosine diphosphate (ADP) is an important platelet agonist that plays a role in hemostasis and pathophysiological arterial thrombosis. 1 ADP causes platelets to undergo shape change, release granule contents, and aggregate. [2][3][4] Upon exposure to activating agonists, such as ADP, platelets hydrolyze arachidonic acid from phospholipid and convert it into thromboxane A 2 by sequential oxygenation via cyclo-oxygenase and thromboxane A 2 synthase. 5 The released thromboxane A 2 acts as a positive feedback mediator in the activation and recruitment of more platelets to the primary hemostatic plug. 6 ADP also causes adhesion of platelets to vitronectin or osteopontin, which might play an important role in anchoring platelets to disrupted atherosclerotic plaques and to the walls of the injured arteries. 7 All the ADP-induced intracellular signaling events, viz, rapid influx of calcium, activation of phospholipase C, mobilization of calcium from intracellular stor...

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Section: Effect Of Outside-in Signaling On Thromboxane a 2 Generationmentioning

confidence: 99%

Adenosine diphosphate (ADP)–induced thromboxane A2generation in human platelets requires coordinated signaling through integrin αIIbβ3 and ADP receptors

Jin

Quinton

Zhang

et al. 2002

Blood

152

114

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“…It promotes further platelet activation by interacting with its G q ‐coupled TP (Thromboxane–Prostanoid) receptor [1,2]. TXA 2 levels have been found to be elevated in patients suffering from myocardial infarction (MI) [3]. Correspondingly, TP receptor [4] or prostaglandin H synthase 1 (PGHS1) null mice [5] present with bleeding diatheses and are refractory to TXA 2 or AA‐induced thromboembolism.…”

Section: Introductionmentioning

confidence: 99%

P2Y12 receptor‐mediated potentiation of thrombin‐induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation

Shankar¹,

Garcia²,

Prabhakar³

et al. 2006

Journal of Thrombosis and Haemostasis

111

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Summary. Background: Thromboxane A 2 (TXA 2 ) is a positive feedback lipid mediator that is generated upon stimulation of platelets with various agonists. Aspirin works as an antithrombotic drug by blocking the generation of TXA 2 . The aim of this study was to evaluate the role of the purinergic P2Y receptors in thrombin-induced TXA 2 generation. Results: PAR1-activating peptide (SFLLRN), PAR4-activating peptide (AYPGKF), and thrombin, induced the activation of cytosolic phospholipase A 2 (cPLA 2 ), release of arachidonic acid (AA) from membranebound phospholipids, and subsequent TXA 2 generation in human platelets. The actions of these agonists were significantly inhibited in the presence of the P2Y 12 receptor antagonist, AR-C69931MX, but not the P2Y 1 receptor antagonist, MRS2179. In addition, AYPGKF-and thrombin-induced TXA 2 generation was significantly reduced in platelets from mice dosed with clopidogrel, confirming the results obtained with the human platelets. Also, Pearl mouse platelets that lack releasable nucleotides generated significantly less TXA 2 when compared with the wild-type littermates in response to PAR stimulation. Inhibition of extracellular signal-regulated protein kinase 1/2 (Erk 1/2) activation using U0126, an inhibitor of MAP kinase kinase (MEK), suppressed PAR-mediated cPLA 2 phosphorylation and TXA 2 generation. Further, platelets that were pretreated with AR-C69931MX, as well as Pearl mouse platelets, displayed the reduced levels of Erk1/2 phosphorylation upon stimulation with the PAR agonists. Conclusions: Based on these findings, we conclude that thrombin-induced Erk1/2 activation is essential for PAR-mediated TXA 2 generation, which is potentiated by the P2Y 12 receptor-mediated signaling pathway but not the P2Y 1 receptor-mediated signaling pathway. Finally, using selective inhibitors of Src kinases, we show that PAR-mediated Src activation precedes Erk1/2 activation.

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“…Apart from activating platelets, TXA 2 is also known to be a potent vaso-constrictor. TXA 2 generation was found to be elevated in patients with myocardial infarction [77] and therefore aspirin, a non-selective cyclooxygenase (COX) inhibitor has gained enormous recognition as an antiplatelet agent and is commonly used in the management of patients with acute coronary syndromes or prevention of cerebro-vascular accidents in patients with risk factors. Aspirin acetylates COX at serine 529 residue and prevents its interaction with AA and therefore inhibits the generation of TXA 2 .…”

Section: Thromboxane-prostanoid (Tp) Receptormentioning

confidence: 99%

G-protein Dependent Platelet Signaling - Perspectives for Therapy

Shankar¹,

Kahner²,

Kunapuli³

2006

CDT

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Platelet activation and aggregation is an integral component of the pathophysiology that leads to thrombotic and ischemic diseases such as cerebral stroke, peripheral vascular disease and myocardial infarction. Anti-platelet agents (such as aspirin, ADP receptor antagonists, and GPIIb/IIIa antagonists), phosphodiesterase inhibitors and anti-coagulants are major part of the current treatment towards treating ischemic diseases. However, their limited efficacy in the setting of arterial thrombosis, unfavorable side effect profile and cost-to-benefit issues substantiate the need for the development of newer and more efficacious antithrombotic drugs. Various platelet agonists like adenosine diphosphate (ADP), thrombin and thromboxane A2 (TXA2) activate platelets by acting via their respective surface receptors, which couple to one or more distinct G-proteins belonging to either the G(i), G(q), G(12/13) or G(s) families. Upon activation, each of these G-proteins trigger a series of intracellular signaling cascades, causing the platelets to undergo shape change, secrete their granular contents, generate positive feedback mediators and form stable platelet aggregates. In addition, various G-protein-mediated signaling cascades act in synergy with one another to amplify the magnitude of the platelet responses. The significance of G-proteins as key mediators of the platelet function and normal hemostasis is further corroborated by extensive gene knockout studies. In this review we will limit our discussion to understanding the role of G-proteins in the process of platelet activation and discuss some of the anti-thrombotic drugs that mediate their beneficial effects by interfering with or preventing the initiation of the G-protein signaling pathway.

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Long Term Aspirin in the Prevention of Cardiovascular Disorders

Cited by 10 publications

References 45 publications

Adenosine diphosphate (ADP)–induced thromboxane A2generation in human platelets requires coordinated signaling through integrin αIIbβ3 and ADP receptors

Adenosine diphosphate (ADP)–induced thromboxane A2generation in human platelets requires coordinated signaling through integrin αIIbβ3 and ADP receptors

P2Y12 receptor‐mediated potentiation of thrombin‐induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation

G-protein Dependent Platelet Signaling - Perspectives for Therapy

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