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Science 296 (5567): 539-541

Copyright © 2002 by the American Association for the Advancement of Science

Role of Prostacyclin in the Cardiovascular Response to Thromboxane A2

Yan Cheng,1 Sandra C. Austin,1 Bianca Rocca,1 Beverly H. Koller,2 Thomas M. Coffman,3 Tilo Grosser,1 John A. Lawson,1 Garret A. FitzGerald1*

Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-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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L. Yang, Y. Huang, R. Porta, K. Yanagisawa, A. Gonzalez, E. Segi, D. H. Johnson, S. Narumiya, and D. P. Carbone (2006)
Cancer Res. 66, 9665-9672
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Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis.
M. Wang, A. M. Zukas, Y. Hui, E. Ricciotti, E. Pure, and G. A. FitzGerald (2006)
PNAS 103, 14507-14512
   Abstract »    Full Text »    PDF »
COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis.
A. K. Lovgren, L. A. Jania, J. M. Hartney, K. K. Parsons, L. P. Audoly, G. A. FitzGerald, S. L. Tilley, and B. H. Koller (2006)
Am J Physiol Lung Cell Mol Physiol 291, L144-L156
   Abstract »    Full Text »    PDF »
Disruption of COX-2 modulates gene expression and the cardiac injury response to doxorubicin.
T. G. Neilan, G. A. Doherty, G. Chen, C. Deflandre, H. McAllister, R. K. Butler, S. E. McClelland, E. Kay, L. R. Ballou, and D. J. Fitzgerald (2006)
Am J Physiol Heart Circ Physiol 291, H532-H536
   Abstract »    Full Text »    PDF »
Effect of Enteric Coating on Antiplatelet Activity of Low-Dose Aspirin in Healthy Volunteers.
D. Cox, A. O. Maree, M. Dooley, R. Conroy, M. F. Byrne, and D. J. Fitzgerald (2006)
Stroke 37, 2153-2158
   Abstract »    Full Text »    PDF »
Increased systolic blood pressure with rofecoxib in congenital furosemide-like salt loss.
M. Komhoff, G. Klaus, S. Nazarowa, S. C. Reinalter, and H. W. Seyberth (2006)
Nephrol. Dial. Transplant. 21, 1833-1837
   Abstract »    Full Text »    PDF »
Protection of Endothelial Survival by Peroxisome Proliferator-Activated Receptor-{delta} Mediated 14-3-3 Upregulation.
J.-Y. Liou, S. Lee, D. Ghelani, N. Matijevic-Aleksic, and K. K. Wu (2006)
Arterioscler Thromb Vasc Biol 26, 1481-1487
   Abstract »    Full Text »    PDF »
Adventures in vascular biology: a tale of two mediators.
S. Moncada (2006)
Phil Trans R Soc B 361, 735-759
   Abstract »    Full Text »    PDF »
Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression.
T. G. Neilan, D. S. Jassal, M. F. Scully, G. Chen, C. Deflandre, H. McAllister, E. Kay, S. C. Austin, E. F. Halpern, J. H. Harmey, et al. (2006)
Eur. Heart J. 27, 1251-1256
   Abstract »    Full Text »    PDF »
Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo.
P. Patrignani, C. Di Febbo, S. Tacconelli, V. Moretta, G. Baccante, M. G. Sciulli, E. Ricciotti, M. L. Capone, I. Antonucci, M. D. Guglielmi, et al. (2006)
Blood 107, 3572-3574
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Internalization and Recycling of the Human Prostacyclin Receptor Is Modulated through Its Isoprenylation-dependent Interaction with the {delta} Subunit of cGMP Phosphodiesterase 6.
S. J. Wilson and E. M. Smyth (2006)
J. Biol. Chem. 281, 11780-11786
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The G12 Family of G Proteins as a Reporter of Thromboxane A2 Receptor Activity.
L. Zhang, C. DiLizio, D. Kim, E. M. Smyth, and D. R. Manning (2006)
Mol. Pharmacol. 69, 1433-1440
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Thromboxane A2-induced arrhythmias in the anesthetized rabbit.
M. J. Wacker, S. R. Best, L. M. Kosloski, C. J. Stachura, R. L. Smoot, C. B. Porter, and J. A. Orr (2006)
Am J Physiol Heart Circ Physiol 290, H1353-H1361
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The prostacyclin receptor induces human vascular smooth muscle cell differentiation via the protein kinase A pathway.
K. M. Fetalvero, M. Shyu, A. P. Nomikos, Y.-F. Chiu, R. J. Wagner, R. J. Powell, J. Hwa, and K. A. Martin (2006)
Am J Physiol Heart Circ Physiol 290, H1337-H1346
   Abstract »    Full Text »    PDF »
Thromboxane A2/Prostaglandin H2 Receptor Activation Mediates Angiotensin II-Induced Postischemic Neovascularization.
F. Michel, J.-S. Silvestre, L. Waeckel, S. Corda, T. Verbeuren, J. P. Vilaine, M. Clergue, M. Duriez, and B. I. Levy (2006)
Arterioscler Thromb Vasc Biol 26, 488-493
   Abstract »    Full Text »    PDF »
Targeting Prostaglandin E2 Receptors as an Alternative Strategy to Block Cyclooxygenase-2-dependent Extracellular Matrix-induced Matrix Metalloproteinase-9 Expression by Macrophages.
S. Pavlovic, B. Du, K. Sakamoto, K. M. F. Khan, C. Natarajan, R. M. Breyer, A. J. Dannenberg, and D. J. Falcone (2006)
J. Biol. Chem. 281, 3321-3328
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