Circulation. 2002;105:1816-1823
Published online before print April 8, 2002, doi: 10.1161/01.CIR.0000014927.74465.7F
Published online before print April 8, 2002, doi: 10.1161/01.CIR.0000014927.74465.7F
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;105:1816.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Cyclooxygenase-2 Promotes Early Atherosclerotic Lesion Formation in LDL Receptor–Deficient Mice
From the Departments of Pharmacology (M.E.B., J.A.O., J.D.M., M.F.L.), Medicine (V.R.B., J.A.O., R.C.H., J.D.M., S.F., M.F.L.), Preventive Medicine (S.G.), Biochemistry (L.J.M.), and Pathology (S.F.), Vanderbilt University Medical Center, Nashville, Tenn; and Merck Frosst (D.R.), Centre for Therapeutic Research, Kirkland, Quebec.
*These authors contributed equally to this study.
This article originally appeared Online on April 8, 2002 (Circulation. 2002;105:r53–r60).Correspondence to Dr MacRae F. Linton or Dr Sergio Fazio, Cardiovascular Medicine, Vanderbilt University School of Medicine, 383 Preston Research Building, Nashville, TN 37232-6300. E-mail macrae.linton{at}mcmail.vanderbilt.edu or sergio.fazio@mcmail.vanderbuilt.edu
Background— Atherosclerosis has features of an inflammatory disease. Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor–deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice.
Methods and Results— Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin for 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in the aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1–mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF1
. Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macrophages. After 8 weeks on the Western diet, COX-2-/-
LDLR-/- mice developed significantly less (33% to 39%) atherosclerosis than control COX-2+/+LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups.
Conclusions— The present studies provide strong pharmacological and genetic evidence that COX-2 promotes early atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflammatory approaches to the prevention of atherosclerosis. (Circulation. 2002;105:1816-1823.)
Key Words: atherosclerosis • inflammation • mice • macrophage • transplantation
This article has been cited by other articles:
 |
|
 |
|
  K. Taketa, T. Matsumura, M. Yano, N. Ishii, T. Senokuchi, H. Motoshima, Y. Murata, S. Kim-Mitsuyama, T. Kawada, H. Itabe, et al. Oxidized Low Density Lipoprotein Activates Peroxisome Proliferator-activated Receptor-{alpha} (PPAR{alpha}) and PPAR{gamma} through MAPK-dependent COX-2 Expression in Macrophages J. Biol. Chem., April 11, 2008; 283(15): 9852 - 9862. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kawai, T. Nishikawa, Y. Shiba, S. Saito, K. Murota, N. Shibata, M. Kobayashi, M. Kanayama, K. Uchida, and J. Terao Macrophage as a Target of Quercetin Glucuronides in Human Atherosclerotic Arteries: IMPLICATION IN THE ANTI-ATHEROSCLEROTIC MECHANISM OF DIETARY FLAVONOIDS J. Biol. Chem., April 4, 2008; 283(14): 9424 - 9434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Deeb, R. K. Upmacis, B. D. Lamon, S. S. Gross, and D. P. Hajjar Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways: Promising Offensives Against Vascular Injury Hypertension, January 1, 2008; 51(1): 1 - 7. [Full Text] [PDF]
|
|
|
|
|
|
K. Xu, C. M. Kitchen, H.-K. G. Shu, and T. J. Murphy Platelet-derived Growth Factor-induced Stabilization of Cyclooxygenase 2 mRNA in Rat Smooth Muscle Cells Requires the c-Src Family of Protein-tyrosine Kinases J. Biol. Chem., November 9, 2007; 282(45): 32699 - 32709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Salinas, U. C. Rangasetty, B. F. Uretsky, and Y. Birnbaum The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 98 - 111. [Abstract] [PDF]
|
|
|
|
 |
|
 E. M. Antman, J. S. Bennett, A. Daugherty, C. Furberg, H. Roberts, and K. A. Taubert Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians: A Scientific Statement From the American Heart Association Circulation, March 27, 2007; 115(12): 1634 - 1642. [Full Text] [PDF]
|
|
|
|
|
|
L. Timmers, J. P.G. Sluijter, C. W.J. Verlaan, P. Steendijk, M. J. Cramer, M. Emons, C. Strijder, P. F. Grundeman, S. K. Sze, L. Hua, et al. Cyclooxygenase-2 Inhibition Increases Mortality, Enhances Left Ventricular Remodeling, and Impairs Systolic Function After Myocardial Infarction in the Pig Circulation, January 23, 2007; 115(3): 326 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cuenca, P. Martin-Sanz, A. M. Alvarez-Barrientos, L. Bosca, and N. Goren Infiltration of Inflammatory Cells Plays an Important Role in Matrix Metalloproteinase Expression and Activation in the Heart during Sepsis Am. J. Pathol., November 1, 2006; 169(5): 1567 - 1576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Massaro, A. Habib, L. Lubrano, S. D. Turco, G. Lazzerini, T. Bourcier, B. B. Weksler, and R. De Caterina The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC{varepsilon} inhibition PNAS, October 10, 2006; 103(41): 15184 - 15189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wang, A. M. Zukas, Y. Hui, E. Ricciotti, E. Pure, and G. A. FitzGerald Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis PNAS, September 26, 2006; 103(39): 14507 - 14512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-l. Li, M. A. Reddy, Q. Cai, L. Meng, H. Yuan, L. Lanting, and R. Natarajan Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice Diabetes, September 1, 2006; 55(9): 2611 - 2619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-G. Deng, S.-T. Tang, H.-P. Tseng, and K. K. Wu Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding Blood, July 15, 2006; 108(2): 518 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Alfranca, M. A. Iniguez, M. Fresno, and J. M. Redondo Prostanoid signal transduction and gene expression in the endothelium: Role in cardiovascular diseases Cardiovasc Res, June 1, 2006; 70(3): 446 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Bishop-Bailey, J. A. Mitchell, and T. D. Warner COX-2 in cardiovascular disease. Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 956 - 958. [Full Text] [PDF]
|
|
|
|
|
|
V. L. King, D. B. Trivedi, J. M. Gitlin, and C. D. Loftin Selective Cyclooxygenase-2 Inhibition With Celecoxib Decreases Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1137 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Dronadula, F. Rizvi, E. Blaskova, Q. Li, and G. N. Rao Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility J. Lipid Res., April 1, 2006; 47(4): 767 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Harris and M. D. Breyer Update on Cyclooxygenase-2 Inhibitors Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 236 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pavlovic, B. Du, K. Sakamoto, K. M. F. Khan, C. Natarajan, R. M. Breyer, A. J. Dannenberg, and D. J. Falcone Targeting Prostaglandin E2 Receptors as an Alternative Strategy to Block Cyclooxygenase-2-dependent Extracellular Matrix-induced Matrix Metalloproteinase-9 Expression by Macrophages J. Biol. Chem., February 10, 2006; 281(6): 3321 - 3328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Deng, S.-p. Zhao, H.-y. Dai, X.-s. Guan, and H.-g. Huang Atorvastatin Reduces the Expression of COX-2 mRNA in Peripheral Blood Monocytes from Patients with Acute Myocardial Infarction and Modulates the Early Inflammatory Response Clin. Chem., February 1, 2006; 52(2): 300 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. R. Babaev, L. Ding, J. Reese, J. D. Morrow, M. D. Breyer, S. K. Dey, S. Fazio, and M. F. Linton Cyclooxygenase-1 Deficiency in Bone Marrow Cells Increases Early Atherosclerosis in Apolipoprotein E- and Low-Density Lipoprotein Receptor-Null Mice Circulation, January 3, 2006; 113(1): 108 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-p. Zhao, P. Deng, H.-g. Huang, Z.-m. Xu, H.-y. Dai, S.-c. Hong, J. Yang, and H.-n. Zhou Expression of COX-2 mRNA in Peripheral Blood Monocytes from Patients with Acute Myocardial Infarction and Its Significance Clin. Chem., November 1, 2005; 51(11): 2170 - 2173. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fosslien Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 347 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Mezzetti Pharmacological modulation of plaque instability Lupus, September 1, 2005; 14(9): 769 - 772. [Abstract] [PDF]
|
|
|
|
|
|
F. Cipollone, M. L. Fazia, A. Iezzi, C. Cuccurullo, D. De Cesare, S. Ucchino, F. Spigonardo, A. Marchetti, F. Buttitta, L. Paloscia, et al. Association Between Prostaglandin E Receptor Subtype EP4 Overexpression and Unstable Phenotype in Atherosclerotic Plaques in Human Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1925 - 1931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. F. McAdam, D. Byrne, J. D. Morrow, and J. A. Oates Contribution of Cyclooxygenase-2 to Elevated Biosynthesis of Thromboxane A2 and Prostacyclin in Cigarette Smokers Circulation, August 16, 2005; 112(7): 1024 - 1029. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Antman, D. DeMets, and J. Loscalzo Cyclooxygenase Inhibition and Cardiovascular Risk Circulation, August 2, 2005; 112(5): 759 - 770. [Full Text] [PDF]
|
|
|
|
|
|
M. P.J. de Winther, E. Kanters, G. Kraal, and M. H. Hofker Nuclear Factor {kappa}B Signaling in Atherogenesis Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 904 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Liu, C. Zhang, N. Dronadula, Q. Li, and G. N. Rao Blockade of Nuclear Factor of Activated T Cells Activation Signaling Suppresses Balloon Injury-induced Neointima Formation in a Rat Carotid Artery Model J. Biol. Chem., April 15, 2005; 280(15): 14700 - 14708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Bennett, A. Daugherty, D. Herrington, P. Greenland, H. Roberts, and K. A. Taubert The Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): A Science Advisory From the American Heart Association Circulation, April 5, 2005; 111(13): 1713 - 1716. [Full Text] [PDF]
|
|
|
|
|
|
K. K. Wu, J.-Y. Liou, and K. Cieslik Transcriptional Control of COX-2 via C/EBP{beta} Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 679 - 685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Kimmel, J. A. Berlin, M. Reilly, J. Jaskowiak, L. Kishel, J. Chittams, and B. L. Strom Patients Exposed to Rofecoxib and Celecoxib Have Different Odds of Nonfatal Myocardial Infarction Ann Intern Med, February 1, 2005; 142(3): 157 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Egan, M. Wang, M. B. Lucitt, A. M. Zukas, E. Pure, J. A. Lawson, and G. A. FitzGerald Cyclooxygenases, Thromboxane, and Atherosclerosis: Plaque Destabilization by Cyclooxygenase-2 Inhibition Combined With Thromboxane Receptor Antagonism Circulation, January 25, 2005; 111(3): 334 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Beloqui, J. A. Paramo, J. Orbe, A. Benito, I. Colina, A. Monasterio, and J. Diez Monocyte cyclooxygenase-2 overactivity: a new marker of subclinical atherosclerosis in asymptomatic subjects with cardiovascular risk factors? Eur. Heart J., January 2, 2005; 26(2): 153 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fries and T. Grosser The Cardiovascular Pharmacology of COX-2 Inhibition Hematology, January 1, 2005; 2005(1): 445 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Rue, M. A. Jarvis, A. J. Knoche, H. L. Meyers, V. R. DeFilippis, S. G. Hansen, M. Wagner, K. Fruh, D. G. Anders, S. W. Wong, et al. A Cyclooxygenase-2 Homologue Encoded by Rhesus Cytomegalovirus Is a Determinant for Endothelial Cell Tropism J. Virol., November 15, 2004; 78(22): 12529 - 12536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Natarajan and J. L. Nadler Lipid Inflammatory Mediators in Diabetic Vascular Disease Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1542 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bogaty, J. M. Brophy, M. Noel, L. Boyer, S. Simard, F. Bertrand, and G. R. Dagenais Impact of Prolonged Cyclooxygenase-2 Inhibition on Inflammatory Markers and Endothelial Function in Patients With Ischemic Heart Disease and Raised C-Reactive Protein: A Randomized Placebo-Controlled Study Circulation, August 24, 2004; 110(8): 934 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Michelsen, M. H. Wong, P. K. Shah, W. Zhang, J. Yano, T. M. Doherty, S. Akira, T. B. Rajavashisth, and M. Arditi Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E PNAS, July 20, 2004; 101(29): 10679 - 10684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Paoletti, A. M. Gotto Jr, and D. P. Hajjar Inflammation in Atherosclerosis and Implications for Therapy Circulation, June 15, 2004; 109(23_suppl_1): III-20 - III-26. [Abstract] [Full Text]
|
|
|
|
|
|
J. T. Willerson and P. M. Ridker Inflammation as a Cardiovascular Risk Factor Circulation, June 1, 2004; 109(21_suppl_1): II-2 - II-10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. F. Khan, L. R. Howe, and D. J. Falcone Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression J. Biol. Chem., May 21, 2004; 279(21): 22039 - 22046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Solomon, S. Schneeweiss, R. J. Glynn, Y. Kiyota, R. Levin, H. Mogun, and J. Avorn Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults Circulation, May 4, 2004; 109(17): 2068 - 2073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, M. Fazia, A. Iezzi, B. Pini, C. Cuccurullo, M. Zucchelli, D. de Cesare, S. Ucchino, F. Spigonardo, M. De Luca, et al. Blockade of the Angiotensin II Type 1 Receptor Stabilizes Atherosclerotic Plaques in Humans by Inhibiting Prostaglandin E2-Dependent Matrix Metalloproteinase Activity Circulation, March 30, 2004; 109(12): 1482 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sussmann, M. Sarbia, J. Meyer-Kirchrath, R.M. Nusing, K. Schror, and J.W. Fischer Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins Circ. Res., March 19, 2004; 94(5): 592 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shanmugam, I. T. Gaw Gonzalo, and R. Natarajan Molecular Mechanisms of High Glucose-Induced Cyclooxygenase-2 Expression in Monocytes Diabetes, March 1, 2004; 53(3): 795 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, B. Rocca, and C. Patrono Cyclooxygenase-2 Expression and Inhibition in Atherothrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 246 - 255. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. H. Dwyer, H. Allayee, K. M. Dwyer, J. Fan, H. Wu, R. Mar, A. J. Lusis, and M. Mehrabian Arachidonate 5-Lipoxygenase Promoter Genotype, Dietary Arachidonic Acid, and Atherosclerosis N. Engl. J. Med., January 1, 2004; 350(1): 29 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. A. Belton, A. Duffy, S. Toomey, and D. J. Fitzgerald Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis Circulation, December 16, 2003; 108(24): 3017 - 3023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Title, K. Giddens, M. M. McInerney, M. J. McQueen, and B. A. Nassar Effect of cyclooxygenase-2 inhibition with rofecoxib on endothelial dysfunction and inflammatory markers in patients with coronary artery disease J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1747 - 1753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Verma and P. E. Szmitko Coxibs and the endothelium J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1754 - 1756. [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Hankey and J. W. Eikelboom Cyclooxygenase-2 Inhibitors: Are They Really Atherothrombotic, and If Not, Why Not? Stroke, November 1, 2003; 34(11): 2736 - 2740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bea, E. Blessing, B. J Bennett, C. C. Kuo, L. A. Campbell, J. Kreuzer, and M. E Rosenfeld Chronic inhibition of cyclooxygenase-2 does not alter plaque composition in a mouse model of advanced unstable atherosclerosis Cardiovasc Res, October 15, 2003; 60(1): 198 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shanmugam, Y. S. Kim, L. Lanting, and R. Natarajan Regulation of Cyclooxygenase-2 Expression in Monocytes by Ligation of the Receptor for Advanced Glycation End Products J. Biol. Chem., September 12, 2003; 278(37): 34834 - 34844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Tuleja, F. Mejza, A. Cmiel, and A. Szczeklik Effects of Cyclooxygenases Inhibitors on Vasoactive Prostanoids and Thrombin Generation at the Site of Microvascular Injury in Healthy Men Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 1111 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Belton and D. Fitzgerald Cyclooxygenase-2 inhibitors and atherosclerosis J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1820 - 1822. [Full Text] [PDF]
|
|