Platelet Adherence to Collagen: Role of Prostaglandin—Thromboxane Synthesis

Cowan, Dale H.

doi:10.1111/j.1365-2141.1981.tb07245.x

Cited by 31 publications

(16 citation statements)

References 16 publications

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“…Given that patients with juvenile arthritis in Western countries are likely to consume COX-2 inhibitors for extended periods while they consume an atherogenic diet, we felt it was important to address this aspect of drug action. On the other hand, platelet COX-1 is a prominent source of TxA 2 , a platelet agonist and vasoconstrictor that stimulates vascular smooth-muscle cell adhesion, migration, and proliferation (43)(44)(45). Remarkably little information is available on the clinical effects of isoformnonspecific inhibitors such as indomethacin or aspirin on atherosclerotic plaque progression in humans.…”

Section: Discussionmentioning

confidence: 99%

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

Praticò

Cyrus²,

Zhang³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

206

150

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The cyclooxygenase (COX) product, prostacyclin (PGI2), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI 2 biosynthesis substantially in humans. Because deletion of the PGI 2 receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF 1␣ by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI 2 biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 ؎ 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and͞or aspirin on plaque progression in humans is timely. P latelet-dependent vascular occlusion complicating fracture of an atherosclerotic plaque is thought to be the pathophysiological basis of both acute myocardial infarction and the majority of cases of stroke (1, 2). The efficacy of plateletinhibitory drugs-aspirin (3-5), clopidogrel (6), and dipyridamole (7)-in the secondary prevention of coronary and cerebrovascular disease has been established in randomized controlled clinical trials. Much less is known about the potential contribution of platelet activation to development and progression of the underlying atherosclerotic disease. Although platelets release mitogenic growth factors and bioactive lipids when activated (8, 9), their relative absence in the descriptive morphology of atherosclerotic lesions in humans has led to a reduction in emphasis on their role in pathogenesis (10). Therefore, such studies do not address the possibility that platelets activated in the circulation of patients with atherosclerosis (11) might release products that modulate lesion progression, and controlled clinical trials of antiplatelet agents on plaque progression have not been performed. Similarly, mouse models of atherosclerosis seem quite resistant to spontaneous thrombosis (12), and it is unknown whether their development of vascular lesions alone results in platelet ac...

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Section: Discussionmentioning

confidence: 99%

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

Praticò

Cyrus²,

Zhang³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

206

150

View full text Add to dashboard Cite

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“…Based on previous reports showing that collagen-induced aggregation strongly depends on feedback by endogenous TxA 2 , 57,58 we speculated that the aggregation/adhesion defects of CalDAG-GEFI Ϫ/Ϫ platelets to collagen 16 could be overcome by adding exogenous TxA 2 . Indeed, we were able to restore GPVI-dependent aggregation of CalDAG-GEFI Ϫ/Ϫ platelets by adding U46619 (Figure 4A) or TxA 2 released from WT platelets ( Figure 5).…”

Section: Caldag-gefi In Platelet Calciummentioning

confidence: 99%

CalDAG-GEFI is at the nexus of calcium-dependent platelet activation

Stefanini

Roden

Bergmeier

2009

Blood

137

150

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The importance of the second messengers calcium (Ca 2؉ ) and diacylglycerol (DAG) in platelet signal transduction was established more than 30 years ago. Whereas protein kinase C (PKC) family members were discovered as the targets of DAG, little is known about the molecular identity of the main Ca 2؉ sensor(s). We here identify Ca 2؉ and DAG-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) as a critical molecule in Ca 2؉ -dependent platelet activation. CalDAG-GEFI, through activation of the small GTPase Rap1, directly triggers integrin activation and extracellular signalregulated kinase-dependent thromboxane A 2 (TxA 2 ) release. CalDAG-GEFIdependent TxA 2 generation provides crucial feedback for PKC activation and granule release, particularly at threshold agonist concentrations. PKC/P2Y12 signaling in turn mediates a second wave of Rap1 activation, necessary for sustained platelet activation and thrombus stabilization. Our results lead to a revised model for platelet activation that establishes one molecule, CalDAG-GEFI, at the nexus of Ca 2؉ -induced integrin activation, TxA 2 generation, and granule release. The preferential activation of CalDAG-GEFI over PKC downstream of phospholipase C activation, and the different kinetics of CalDAG-GEFI-and PKC/P2Y12-mediated Rap1 activation demonstrate an unexpected complexity to the platelet activation process, and they challenge the current model that DAG/PKC-dependent signaling events are crucial for the initiation of platelet adhesion. IntroductionPlatelet thrombus formation at sites of vascular injury is a complex and dynamic process that occurs in several phases. 1,2 Platelet preactivation and tethering (transient adhesion) are mediated by the interaction of glycoprotein (GP) lb␣ with matrix-bound von Willebrand factor, particularly in conditions of high shear. Platelet activation and firm adhesion are then triggered by collagen exposed in the vessel wall and/or locally generated thrombin. Sustained integrin activation and the formation of stable thrombi further depend on persistent costimulatory signaling provided by the second wave agonists, thromboxane A 2 (TxA 2 ) and adenosine 5Ј-diphosphate (ADP), which are released from activated platelets. [3][4][5] The central biochemical event in platelet aggregation is the agonist-induced inside-out activation of ␣ IIb ␤ 3 integrin. Most platelet agonists initiate intracellular signaling through the activation of phospholipase C (PLC), followed by the generation of the second messengers calcium (Ca 2ϩ ) and diacylgycerol (DAG). DAG is critical for protein kinase C (PKC) activation, a key event in platelet granule release and integrin activation. Platelets express at least 6 PKC isoforms, which have activating as well as inhibitory roles in platelet activation. [6][7][8][9][10] Early studies with calcium ionophores established a role of Ca 2ϩ in integrin activation, TxA 2 generation, and granule release. 11-13 Initially, Ca 2ϩ -binding classical isoforms of PKC were suggested as the cell's main signal integ...

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“…Collagen can induce platelet activation through a tyrosine kinase-based signaling pathway that involves the kinase Syk and phospholipase Cγ2. Platelet aggregation is largely dependent on ADP and prostaglandin E 2 /TXA 2 release (Cowan, 1981). The data suggest that complicated pathways may be involved in antiplatelet aggregation activity by indole-3-carbinol.…”

Section: Discussionmentioning

confidence: 87%

Antiplatelet and antithrombotic activity of indole‐3‐carbinol in vitro and in vivo

Park

Rhee

Lee

et al. 2007

Phytotherapy Research

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Indole-3-carbinol, a natural compound found in cruciferous vegetables, is known to have anticancer activity. In the present study, the antiplatelet and antithrombotic activities of indole-3-carbinol were investigated in vitro and in vivo. Indole-3-carbinol significantly inhibited collagen-induced platelet aggregation in human platelet rich plasma (PRP) in a concentration-dependent manner. Indole-3-carbinol significantly inhibited fibrinogen binding to the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa) receptor by flow cytometric analysis. In addition, the levels of thromboxane B 2 (TXB 2 ) and prostaglandin E 2 (PGE 2 ) in collagen stimulated PRP were significantly inhibited in a concentration-dependent manner by indole-3-carbinol. Furthermore, indole-3-carbinol dose-dependently suppressed the death of mice with pulmonary thrombosis induced by intravenous injection of collagen and epinephrine. These results suggest that indole-3-carbinol can be a potent antithrombotic agent with antiplatelet activity through the inhibition of GP IIb/IIIa receptor and thromboxane B 2 formation.

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Platelet Adherence to Collagen: Role of Prostaglandin—Thromboxane Synthesis

Cited by 31 publications

References 16 publications

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

CalDAG-GEFI is at the nexus of calcium-dependent platelet activation

Antiplatelet and antithrombotic activity of indole‐3‐carbinol in vitro and in vivo

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