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Role of Prostacyclin in the Cardiovascular Response to Thromboxane A2
Yan Cheng,1Sandra C. Austin,1Bianca Rocca,1Beverly H. Koller,2Thomas M. Coffman,3Tilo Grosser,1John A. Lawson,1Garret A. FitzGerald1*
Thromboxane (Tx) A2 is a
vasoconstrictor and platelet agonist. Aspirin affords cardioprotection
through inhibition of TxA2formation by platelet
cyclooxygenase (COX-1). Prostacyclin (PGI2)is a
vasodilator that inhibits platelet function. Here we showthat
injury-induced vascular proliferation and platelet activationare
enhanced in mice that are genetically deficient in the PGI2receptor (IP) but are depressed in mice genetically deficientin the
TxA2 receptor (TP) or treated with a TP antagonist.
Theaugmented response to vascular injury was abolished in mice
deficientin both receptors. Thus, PGI2 modulates
platelet-vascular interactionsin vivo and specifically limits the
response to TxA2. This interplaymay help explain the
adverse cardiovascular effects associatedwith selective COX-2
inhibitors, which, unlike aspirin and nonsteroidalanti-inflammatory
drugs (NSAIDs), inhibit PGI2 but not TxA2.
1 Center for Experimental Therapeutics, 153 Johnson Pavilion, 3620 Hamilton Walk, University of Pennsylvania School
of Medicine, Philadelphia, PA 19104-6084, USA.
2 Department of Medicine, University of North
Carolina, Chapel Hill, NC 27559, USA.
3 Department
of Medicine, Duke University, Durham, NC 27705, USA.
*
To whom correspondence should be addressed. E-mail:
garret{at}spirit.gcrc.upenn.edu
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Antiplatelet Activity of J78 (2-Chloro-3-[2'-bromo, 4'-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), an Antithrombotic Agent, Is Mediated by Thromboxane (TX) A2 Receptor Blockade with TXA2 Synthase Inhibition and Suppression of Cytosolic Ca2+ Mobilization.
Y.-R. Jin, M.-R. Cho, C.-K. Ryu, J.-H. Chung, D.-Y. Yuk, J.-T. Hong, K.-S. Lee, J.-J. Lee, M.-Y. Lee, Y. Lim, et al. (2005)
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312, 214-219
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Differential Effects of Vasodilatory Prostaglandins on Focal Adhesions, Cytoskeletal Architecture, and Migration in Human Aortic Smooth Muscle Cells.
C. Bulin, U. Albrecht, J.G. Bode, A.-A. Weber, K. Schror, B. Levkau, and J.W. Fischer (2005)
Arterioscler Thromb Vasc Biol
25, 84-89
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The Cardiovascular Pharmacology of COX-2 Inhibition.
Distinct cAMP signaling pathways differentially regulate {alpha}2C-adrenoceptor expression: role in serum induction in human arteriolar smooth muscle cells.
M. A. Chotani, S. Mitra, A. H. Eid, S. A. Han, and N. A. Flavahan (2005)
Am J Physiol Heart Circ Physiol
288, H69-H76
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Dimerization of the Human Receptors for Prostacyclin and Thromboxane Facilitates Thromboxane Receptor-mediated cAMP Generation.
S. J. Wilson, A. M. Roche, E. Kostetskaia, and E. M. Smyth (2004)
J. Biol. Chem.
279, 53036-53047
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COX-2-Derived Prostacyclin Confers Atheroprotection on Female Mice.
K. M. Egan, J. A. Lawson, S. Fries, B. Koller, D. J. Rader, E. M. Smyth, and G. A. FitzGerald (2004)
Science
306, 1954-1957
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Intravascular Thrombosis After Hypoxia-Induced Pulmonary Hypertension: Regulation by Cyclooxygenase-2.
G. P. Pidgeon, R. Tamosiuniene, G. Chen, I. Leonard, O. Belton, A. Bradford, and D. J. Fitzgerald (2004)
Circulation
110, 2701-2707
|Abstract »|Full Text »|PDF »
Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial.
N. Chiang, E. A. Bermudez, P. M. Ridker, S. Hurwitz, and C. N. Serhan (2004)
PNAS
101, 15178-15183
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Selective Inhibition of Cyclooxygenase-2 Enhances Platelet Adhesion in Hamster Arterioles In Vivo.
M. A. Buerkle, S. Lehrer, H.-Y. Sohn, P. Conzen, U. Pohl, and F. Krotz (2004)
Circulation
110, 2053-2059
|Abstract »|Full Text »|PDF »
Signaling through the Prostaglandin I2 Receptor IP Protects against Respiratory Syncytial Virus-Induced Illness.
K. Hashimoto, B. S. Graham, M. W. Geraci, G. A. FitzGerald, K. Egan, W. Zhou, K. Goleniewska, J. F. O'Neal, J. D. Morrow, R. K. Durbin, et al. (2004)
J. Virol.
78, 10303-10309
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Reduced IP receptors in STZ-induced diabetic rat kidneys and high-glucose-treated mesangial cells.
R. Nasrallah and R. L. Hebert (2004)
Am J Physiol Renal Physiol
287, F673-F681
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Effect of BM-573 [N-Terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a Dual Thromboxane Synthase Inhibitor and Thromboxane Receptor Antagonist, in a Porcine Model of Acute Pulmonary Embolism.
A. Ghuysen, B. Lambermont, J.-M. Dogne, P. Kolh, V. Tchana-Sato, P. Morimont, D. Magis, J. Hanson, P. Segers, and V. D'Orio (2004)
J. Pharmacol. Exp. Ther.
310, 964-972
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Celecoxib, a Cyclooxygenase-2 Inhibitor, Reduces Neointimal Hyperplasia Through Inhibition of Akt Signaling.
H.-M. Yang, H.-S. Kim, K.-W. Park, H.-J. You, S.-I. Jeon, S.-W. Youn, S.-H. Kim, B.-H. Oh, M.-M. Lee, Y.-B. Park, et al. (2004)
Circulation
110, 301-308
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Antimitogenesis Linked to Regulation of Skp2 Gene Expression.
S. A. Stewart, D. Kothapalli, Y. Yung, and R. K. Assoian (2004)
J. Biol. Chem.
279, 29109-29113
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