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Science 306 (5703): 1954-1957

Copyright © 2004 by the American Association for the Advancement of Science

COX-2-Derived Prostacyclin Confers Atheroprotection on Female Mice

Karine M. Egan,1 John A. Lawson,1 Susanne Fries,1 Beverley Koller,2 Daniel J. Rader,1 Emer M. Smyth,1 Garret A. FitzGerald1*

Abstract: Female gender affords relative protection from cardiovascular disease until the menopause. We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacyclin, PGI2, by activation of cyclooxygenase 2 (COX-2). This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice. Deletion of the PGI2 receptor removed the atheroprotective effect of estrogen in ovariectomized female mice. This suggests that chronic treatment of patients with selective inhibitors of COX-2 could undermine protection from cardiovascular disease in premenopausal females.

1 The Institute for Translational Medicine and Therapeutics, University of Pennsylvania, PA 19104, USA.
2 Department of Medicine, University of North Carolina, NC 27599, USA.

* To whom correspondence should be addressed. E-mail: garret{at}

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C. Li, P.-S. Lee, Y. Sun, X. Gu, E. Zhang, Y. Guo, C.-L. Wu, N. Auricchio, C. Priolo, J. Li, et al. (2014)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. O. Jobe, J. Ramadoss, A. J. Wargin, and R. R. Magness (2013)
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   Abstract »    Full Text »    PDF »
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L. Chen, G. Yang, X. Xu, G. Grant, J. A. Lawson, M. Bohlooly-Y, and G. A. FitzGerald (2013)
Circulation 127, 233-243
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Regulation of the human prostacyclin receptor gene by the cholesterol-responsive SREBP1.
E. C. Turner and B. T. Kinsella (2012)
J. Lipid Res. 53, 2390-2404
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J.-R. Nofer (2012)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. Wu, S. Duchemin, M.-A. Laplante, J. D. Champlain, and H. Girouard (2011)
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   Abstract »    Full Text »    PDF »
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J. A. Oates (2011)
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   Abstract »    Full Text »    PDF »
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R. K. Upmacis, H. Shen, L. E. S. Benguigui, B. D. Lamon, R. S. Deeb, K. A. Hajjar, and D. P. Hajjar (2011)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Stitham, E. Arehart, L. Elderon, S. R. Gleim, K. Douville, Z. Kasza, K. Fetalvero, T. MacKenzie, J. Robb, K. A. Martin, et al. (2011)
J. Biol. Chem. 286, 7060-7069
   Abstract »    Full Text »    PDF »
Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells.
J.-P. Liu, M. Komachi, H. Tomura, C. Mogi, A. Damirin, M. Tobo, M. Takano, H. Nochi, K. Tamoto, K. Sato, et al. (2010)
Am J Physiol Heart Circ Physiol 299, H731-H742
   Abstract »    Full Text »    PDF »
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J.-F. Arnal, C. Fontaine, A. Billon-Gales, J. Favre, H. Laurell, F. Lenfant, and P. Gourdy (2010)
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   Abstract »    Full Text »    PDF »
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C. Bolego, G. Rossoni, G. P. Fadini, E. Vegeto, C. Pinna, M. Albiero, E. Boscaro, C. Agostini, A. Avogaro, R. M. Gaion, et al. (2010)
FASEB J 24, 2262-2272
   Abstract »    Full Text »    PDF »
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Y. Hui, E. Ricciotti, I. Crichton, Z. Yu, D. Wang, J. Stubbe, M. Wang, E. Pure, and G. A. FitzGerald (2010)
Circulation 121, 2654-2660
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J.-i. Kawabe, K.-i. Yuhki, M. Okada, T. Kanno, A. Yamauchi, N. Tashiro, T. Sasaki, S. Okumura, N. Nakagawa, Y. Aburakawa, et al. (2010)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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F. Krotz (2009)
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   Full Text »    PDF »
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N. J. Skill, N. G. Theodorakis, Y. N. Wang, J. M. Wu, E. M. Redmond, and J. V. Sitzmann (2008)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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Development 135, 1179-1187
   Abstract »    Full Text »    PDF »
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M. Wang, E. Lee, W. Song, E. Ricciotti, D. J. Rader, J. A. Lawson, E. Pure, and G. A. FitzGerald (2008)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. Sakao, L. Taraseviciene-Stewart, C. D. Cool, Y. Tada, Y. Kasahara, K. Kurosu, N. Tanabe, Y. Takiguchi, K. Tatsumi, T. Kuriyama, et al. (2007)
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   Abstract »    Full Text »    PDF »
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K. Sander, C. Schulze Horn, C. Briesenick, and D. Sander (2007)
Stroke 38, 2881-2886
   Abstract »    Full Text »    PDF »
COX-2 suppresses tissue factor expression via endocannabinoid-directed PPAR{delta} activation.
M. Ghosh, H. Wang, Y. Ai, E. Romeo, J. P. Luyendyk, J. M. Peters, N. Mackman, S. K. Dey, and T. Hla (2007)
J. Exp. Med. 204, 2053-2061
   Abstract »    Full Text »    PDF »
The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame.
G. Salinas, U. C. Rangasetty, B. F. Uretsky, and Y. Birnbaum (2007)
Journal of Cardiovascular Pharmacology and Therapeutics 12, 98-111
   Abstract »    PDF »
Modulation of COX-2 expression by statins in human monocytic cells.
A. Habib, I. Shamseddeen, M. S. Nasrallah, T. A. Antoun, G. Nemer, J. Bertoglio, R. Badreddine, and K. F. Badr (2007)
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   Abstract »    Full Text »    PDF »
Aspirin and COX-2 Inhibitor Nimesulide Potentiate Adrenergic Contractions of Human Gastroepiploic Artery.
M. Aldasoro, M. D. Mauricio, E. Serna, B. Cortina, P. Medina, G. Segarra, S. Novella, and J. M. Vila (2007)
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   Abstract »    Full Text »    PDF »
Regulation of Thromboxane Receptor Trafficking Through the Prostacyclin Receptor in Vascular Smooth Muscle Cells: Role of Receptor Heterodimerization.
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   Abstract »    Full Text »    PDF »
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M.-E. Gendron, N. Thorin-Trescases, L. Villeneuve, and E. Thorin (2007)
Am J Physiol Heart Circ Physiol 292, H451-H458
   Abstract »    Full Text »    PDF »
Versatility and Differential Roles of Cysteine Residues in Human Prostacyclin Receptor Structure and Function.
J. Stitham, S. R. Gleim, K. Douville, E. Arehart, and J. Hwa (2006)
J. Biol. Chem. 281, 37227-37236
   Abstract »    Full Text »    PDF »
Prostaglandin D2 inhibits TGF-beta1-induced epithelial-to-mesenchymal transition in MDCK cells.
A. Zhang, Z. Dong, and T. Yang (2006)
Am J Physiol Renal Physiol 291, F1332-F1342
   Abstract »    Full Text »    PDF »
Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs..
S. Chaiamnuay, J. J. Allison, and J. R. Curtis (2006)
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   Abstract »    Full Text »    PDF »
Host and Direct Antitumor Effects and Profound Reduction in Tumor Metastasis with Selective EP4 Receptor Antagonism.
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
   Abstract »    Full Text »    PDF »
Selective Agonists of Estrogen Receptor Isoforms: New Perspectives for Cardiovascular Disease.
C. Bolego, E. Vegeto, C. Pinna, A. Maggi, and A. Cignarella (2006)
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   Abstract »    Full Text »    PDF »
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M. Wang, A. M. Zukas, Y. Hui, E. Ricciotti, E. Pure, and G. A. FitzGerald (2006)
PNAS 103, 14507-14512
   Abstract »    Full Text »    PDF »
Sex differences in inflammation and inflammatory pain in cyclooxygenase-deficient mice.
N. L. Chillingworth, S. G. Morham, and L. F. Donaldson (2006)
Am J Physiol Regulatory Integrative Comp Physiol 291, R327-R334
   Abstract »    Full Text »    PDF »
Estrogen and progestagens differentially modulate vascular proinflammatory factors.
L. Sunday, M. M. Tran, D. N. Krause, and S. P. Duckles (2006)
Am J Physiol Endocrinol Metab 291, E261-E267
   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 »
17beta-Estradiol Protects against Oxidative Stress-induced Cell Death through the Glutathione/Glutaredoxin-dependent Redox Regulation of Akt in Myocardiac H9c2 Cells.
Y. Urata, Y. Ihara, H. Murata, S. Goto, T. Koji, J. Yodoi, S. Inoue, and T. Kondo (2006)
J. Biol. Chem. 281, 13092-13102
   Abstract »    Full Text »    PDF »
Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps..
E. M. Poole, J. Bigler, J. Whitton, J. G. Sibert, J. D. Potter, and C. M. Ulrich (2006)
Cancer Epidemiol. Biomarkers Prev. 15, 502-508
   Abstract »    Full Text »    PDF »
Problem of the atherothrombotic potential of non-steroidal anti-inflammatory drugs.
W W Bolten (2006)
Ann Rheum Dis 65, 7-13
   Abstract »    Full Text »    PDF »
Metabolite ligands of estrogen receptor-{beta} reduce primate coronary hyperreactivity.
R. G. Mishra, F. Z. Stanczyk, K. A. Burry, S. Oparil, B. S. Katzenellenbogen, M. L. Nealen, J. A. Katzenellenbogen, and R. K. Hermsmeyer (2006)
Am J Physiol Heart Circ Physiol 290, H295-H303
   Abstract »    Full Text »    PDF »
ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery.
F. Li, C. Zhang, S. Schaefer, A. Estes, and K. U. Malik (2005)
Am J Physiol Heart Circ Physiol 289, H2592-H2601
   Abstract »    Full Text »    PDF »
Atherosclerotic Lesion Development in a Novel Ovary-Intact Mouse Model of Perimenopause.
L. P. Mayer, C. A. Dyer, R. L. Eastgard, P. B. Hoyer, and C. L. Banka (2005)
Arterioscler Thromb Vasc Biol 25, 1910-1916
   Abstract »    Full Text »    PDF »
Cyclooxygenase Inhibition and Cardiovascular Risk.
E. M. Antman, D. DeMets, and J. Loscalzo (2005)
Circulation 112, 759-770
   Full Text »    PDF »
Prostacyclin signaling in the kidney: implications for health and disease.
R. Nasrallah and R. L. Hebert (2005)
Am J Physiol Renal Physiol 289, F235-F246
   Abstract »    Full Text »    PDF »
COX-2-Derived Prostacyclin Modulates Vascular Remodeling.
R. D. Rudic, D. Brinster, Y. Cheng, S. Fries, W.-L. Song, S. Austin, T. M. Coffman, and G. A. FitzGerald (2005)
Circ. Res. 96, 1240-1247
   Abstract »    Full Text »    PDF »
Molecular and Cellular Basis of Cardiovascular Gender Differences.
M. E. Mendelsohn and R. H. Karas (2005)
Science 308, 1583-1587
   Abstract »    Full Text »    PDF »
What Happened to the Coxibs on the Way to the Cardiologist?.
D. S. Alberts, J. D. Potter, M. E. Martinez, L. M. Hess, A. Stopeck, and P. Lance (2005)
Cancer Epidemiol. Biomarkers Prev. 14, 555-556
   Full Text »    PDF »
Sexual Dimorphism in Renal Production of Prostanoids in Spontaneously Hypertensive Rats.
J. C. Sullivan, J. M. Sasser, D. M. Pollock, and J. S. Pollock (2005)
Hypertension 45, 406-411
   Abstract »    Full Text »    PDF »
COX-2 Could Explain Estrogen's Protection Against Atherosclerosis.
Journal Watch Cardiology 2005, 4
   Full Text »
COX-2 Could Explain Estrogen's Protection Against Atherosclerosis.
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   Full Text »

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