(Circulation. 2000;102:840.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis
From the Departments of Clinical Pharmacology and Surgery, Royal College of Surgeons in Ireland, St Stephens Green, Dublin, Ireland.
Correspondence to Dr Desmond J. Fitzgerald, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St Stephens Green, Dublin 2, Ireland. E-mail dfitzgerald{at}rcsi.ie
Background—The formation of prostacyclin (PGI2), thromboxane (TX) A2, and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis.
Methods and Results—The study population consisted of 42
patients with atherosclerosis who were undergoing
surgical revascularization. COX-2 mRNA was detected
in areas of atherosclerosis but not in normal blood
vessel walls, and there was evidence of COX-1 induction. The use of
immunohistochemical studies localized the COX-2 to proliferating
vascular smooth muscle cells and macrophages. Twenty-four
patients who did not previously receive aspirin were randomized to
receive either no treatment or nimesulide at 24 hours before surgery
and then for 3 days. Eighteen patients who were receiving aspirin were
continued on a protocol of either aspirin alone or a combination of
aspirin and nimesulide. Urinary levels of 11-dehydro-TXB2
and 2,3-dinor-6-keto-PGF1
, metabolites of
TXA2 and PGI2, respectively, were elevated in
patients with atherosclerosis compared with normal
subjects (3211±533 versus 679±63 pg/mg creatinine,
P<0.001; 594±156 versus 130±22 pg/mg
creatinine, P<0.05, respectively), as was
the level of the isoprostane 8-iso-PGF2. Nimesulide
reduced 2,3-dinor-6-keto-PGF1 excretion by 46±5%
(378.3±103 to 167±37 pg/mg creatinine,
P<0.01) preoperatively and blunted the increase after
surgery. Nimesulide had no significant effect on
11-dehydro-TXB2 before (2678±694 to 2110±282 pg/mg
creatinine) or after surgery. The levels of both
products were lower in patients who were taking aspirin, and no
further reduction was seen with the addition of nimesulide. None of the
treatments influenced urinary 8-iso-PGF2 excretion.
Conclusions—Both COX-1 and -2 are expressed and contribute to the increase in PGI2 in patients with atherosclerosis, whereas TXA2 is generated by COX-1.
Key Words: atherosclerosis • cyclooxygenase • prostaglandins
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 G. Block, M. Dietrich, E. P. Norkus, J. D. Morrow, M. Hudes, B. Caan, and L. Packer Factors Associated with Oxidative Stress in Human Populations Am. J. Epidemiol., August 1, 2002; 156(3): 274 - 285. [Abstract] [Full Text] [PDF]
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 J. A. Ardans, A. P. Economou, J. M. Martinson Jr., M. Zhou, and L. M. Wahl Oxidized low-density and high-density lipoproteins regulate the production of matrix metalloproteinase-1 and -9 by activated monocytes J. Leukoc. Biol., June 1, 2002; 71(6): 1012 - 1018. [Abstract] [Full Text] [PDF]
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L. H. Smith, O. Boutaud, M. Breyer, J. D. Morrow, J. A. Oates, and D. E. Vaughan Cyclooxygenase-2-Dependent Prostacyclin Formation Is Regulated by Low Density Lipoprotein Cholesterol In Vitro Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 983 - 988. [Abstract] [Full Text] [PDF]
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J. Sadoshima Novel AT1 Receptor-Independent Functions of Losartan Circ. Res., April 19, 2002; 90(7): 754 - 756. [Full Text] [PDF]
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C. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]
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A. V. Pontsler, A. St. Hilaire, G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Cyclooxygenase-2 Is Induced in Monocytes by Peroxisome Proliferator Activated Receptor gamma and Oxidized Alkyl Phospholipids from Oxidized Low Density Lipoprotein J. Biol. Chem., April 5, 2002; 277(15): 13029 - 13036. [Abstract] [Full Text] [PDF]
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E. Connolly, D. J. Bouchier-Hayes, E. Kaye, A. Leahy, D. Fitzgerald, and O. Belton Cyclooxygenase Isozyme Expression and Intimal Hyperplasia in a Rat Model of Balloon Angioplasty J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 393 - 398. [Abstract] [Full Text] [PDF]
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M. Yamada, Y. Numaguchi, K. Okumura, M. Harada, K. Naruse, H. Matsui, T. Ito, and T. Hayakawa Prostacyclin Synthase Gene Transfer Modulates Cyclooxygenase-2-Derived Prostanoid Synthesis and Inhibits Neointimal Formation in Rat Balloon-Injured Arteries Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 256 - 262. [Abstract] [Full Text] [PDF]
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M. Dietrich, G. Block, M. Hudes, J. D. Morrow, E. P. Norkus, M. G. Traber, C. E. Cross, and L. Packer Antioxidant Supplementation Decreases Lipid Peroxidation Biomarker F2-isoprostanes in Plasma of Smokers Cancer Epidemiol. Biomarkers Prev., January 1, 2002; 11(1): 7 - 13. [Abstract] [Full Text]
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S. Verma, S. R. Raj, L. Shewchuk, K. J. Mather, and T. J. Anderson Cyclooxygenase-2 Blockade Does Not Impair Endothelial Vasodilator Function in Healthy Volunteers: Randomized Evaluation of Rofecoxib Versus Naproxen on Endothelium-Dependent Vasodilatation Circulation, December 11, 2001; 104(24): 2879 - 2882. [Abstract] [Full Text] [PDF]
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 Z. A. Massy and S. K. Swan Cyclooxygenase-2 and atherosclerosis: friend or foe? Nephrol. Dial. Transplant., December 1, 2001; 16(12): 2286 - 2289. [Full Text] [PDF]
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S. T. Davidge Prostaglandin H Synthase and Vascular Function Circ. Res., October 12, 2001; 89(8): 650 - 660. [Abstract] [Full Text] [PDF]
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G. E. Caughey, L. G. Cleland, P. S. Penglis, J. R. Gamble, and M. J. James Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2 J. Immunol., September 1, 2001; 167(5): 2831 - 2838. [Abstract] [Full Text] [PDF]
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 D. Mukherjee, S. E. Nissen, and E. J. Topol Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors JAMA, August 22, 2001; 286(8): 954 - 959. [Abstract] [Full Text] [PDF]
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F. Cipollone, C. Prontera, B. Pini, M. Marini, M. Fazia, D. De Cesare, A. Iezzi, S. Ucchino, G. Boccoli, V. Saba, et al. Overexpression of Functionally Coupled Cyclooxygenase-2 and Prostaglandin E Synthase in Symptomatic Atherosclerotic Plaques as a Basis of Prostaglandin E2-Dependent Plaque Instability Circulation, August 21, 2001; 104(8): 921 - 927. [Abstract] [Full Text] [PDF]
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C. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]
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J. W. Eikelboom, J. Hirsh, J. I. Weitz, M. Johnston, Q. Yi, and S. Yusuf Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events Circulation, April 9, 2002; 105(14): 1650 - 1655. [Abstract] [Full Text] [PDF]
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M. E. Burleigh, V. R. Babaev, J. A. Oates, R. C. Harris, S. Gautam, D. Riendeau, L. J. Marnett, J. D. Morrow, S. Fazio, and M. F. Linton Cyclooxygenase-2 Promotes Early Atherosclerotic Lesion Formation in LDL Receptor-Deficient Mice Circulation, April 16, 2002; 105(15): 1816 - 1823. [Abstract] [Full Text] [PDF]
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