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Overexpression of COX-2, Prostaglandin E Synthase-1 and Prostaglandin E Receptors in blood mononuclear cells and plaque of patients with carotid atherosclerosis: Regulation by nuclear factor-κB

      Abstract

      Background and objective

      Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) and membrane-associated Prostaglandin E Synthase (mPGES-1) pathway, has been implicated in the instability of atherosclerotic plaques. We have studied COX-2, mPGES-1 and PGE2 receptors (EPs) expression in peripheral blood mononuclear cells (PBMC) and atherosclerotic plaques of 29 patients with carotid stenosis as well as the effect of different nuclear factor-kappaB (NF-κB) inhibitors on COX-2, mPGES-1 and EPs expression in cultured monocytic cells (THP-1).

      Methods

      COX-2, mPGES-1 and EP expression was analyzed by RT-PCR (PBMC), immunohistochemistry (plaques) and Western blot (THP-1). PGE2 levels were determined by ELISA (plasma and cell supernatants).

      Results

      In relation to healthy controls, COX-2, mPGES-1 and EP-3/EP-4 mRNA expression was increased in PBMC from patients. In the inflammatory region of atherosclerotic plaques, an increase of COX-2, mPGES-1 and EPs expression was also observed. Activated NF-κB and COX-2, mPGES-1 and EPs proteins were colocalized in the plaque's cells. In cytokine-treated cultured THP-1, the NF-κB inhibitors parthenolide, Bay 11-7082 and PDTC reduced COX-2, mPGES-1 and EP-1/EP-3/EP-4 expression as well as PGE2 levels. By employing specific agonists and antagonists, we noted that the cytokine- and PGE2-induced metalloproteinase 9 (MMP-9) expression and activity occurs through EP-1/EP-3/EP-4, an effect downregulated by NF-κB inhibitors.

      Conclusions

      Patients with carotid atherosclerosis depict an overexpression of COX-2, mPGES-1 and EPs simultaneously in the PBMC as well as in the vulnerable region of plaques. The studies in cultured monocytic cells suggest that NF-κB inhibitors and/or EPs antagonists could represent a novel therapeutic approach to the treatment of plaque instability and rupture.

      Keywords

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      References

        • Narumiya S.
        • Sugimoto Y.
        • Ushikubi F.
        Prostanoid receptors: structures, properties, and functions.
        Physiol Rev. 1999; 79: 1193-1226
        • Dubois R.N.
        • Abramson S.B.
        • Crofford L.
        • et al.
        Cyclooxygenase in biology and disease.
        FASEB J. 1998; 12: 1063-10673
        • Simon L.S.
        Role and regulation of cyclooxygenase-2 during inflammation.
        Am J Med. 1999; 106: 37S-42S
        • Murakami M.
        • Nakatani Y.
        • Tanioka T.
        • Kudo I.
        Prostaglandin E synthase.
        Prostaglandins Other Lipid Mediat. 2002; 68: 383-399
        • Cipollone F.
        • Prontera C.
        • Pini B.
        • et al.
        Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basic of prostaglandin E(2)-dependent plaque instability.
        Circulation. 2001; 104: 921-927
        • Schonbeck U.
        • Sukhova G.K.
        • Graber P.
        • Coulter S.
        • Libby P.
        Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions.
        Am J Pathol. 1999; 155: 1281-1291
        • Jeziorska M.
        • Woolley D.E.
        Local neovascularization and cellular composition within vulnerable regions of atherosclerotic plaques of human carotid arteries.
        J Pathol. 1999; 188: 189-196
        • Jones C.B.
        • Sane D.C.
        • Herrington D.M.
        Matrix metalloproteinases: a review of their structure and role in acute coronary syndrome.
        Cardiovasc Res. 2003; 59: 812-823
        • Regan J.W.
        EP2 and EP4 prostanoid receptor signaling.
        Life Sci. 2003; 74: 143-153
        • Moon S.K.
        • Cha B.Y.
        • Kim C.H.
        ERK1/2 mediates TNF-alpha-induced MMP-9 expression in human vascular smooth muscle cells via the regulation of NF-kB and AP-1: involvement of the ras dependent pathway.
        J Cell Physiol. 2004; 198: 417-427
        • Collins T.
        • Cybulsky M.I.
        NF-kB: pivotal mediator or innocent bystander in atherogenesis?.
        J Clin Invest. 2001; 107: 255-264
        • Martin-Ventura J.L.
        • Blanco-Colio L.M.
        • Munoz-Garcia B.
        • et al.
        NF-κB activation and fas-ligand overexpression in blood and plaques of patients with carotid atherosclerosis: potential implication in plaque instability.
        Stroke. 2004; 35: 458-463
        • Ritchie M.E.
        Nuclear factor-κB is selectively and markedly activated in humans with unstable angina pectoris.
        Circulation. 1998; 98: 1707-1713
        • Naraba H.
        • Murakami M.
        • Matsumoto H.
        • et al.
        Segregated coupling of phospholipases A2, cyclooxygenases, and terminal prostanoid synthases in different phases of prostanoid biosynthesis in rat peritoneal macrophages.
        J Immunol. 1998; 160: 2974-2982
        • Matsumoto H.
        • Naraba H.
        • Murakami M.
        • et al.
        Concordant induction of prostaglandin E2 synthase with cyclooxygenase-2 leads to preferred production of prostaglandin E2 over thromboxane and prostaglandin D2 in lipopolysaccharide-stimulated rat peritoneal macrophages.
        Biochem Biophys Res Commun. 1997; 230: 110-114
        • Brock T.G.
        • McNish R.W.
        • Peters-Golden M.
        Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2.
        J Biol Chem. 1999; 274: 11660-11666
        • Martin-Ventura J.L.
        • Blanco-Colio L.M.
        • Gómez-Hernández A.
        • et al.
        Intensive treatment with atorvastatin reduces inflammation in mononuclear cells and human atherosclerotic lesion in one month.
        Stroke. 2005; 36: 1796-1800
        • Zeng Li
        • An S.
        • Goetzl E.J.
        Regulation of expression of MMP-9 in early human T cells of HSB.2 cultured line by the EP-3 subtype of prostaglandin E2 receptor.
        J Biol Chem. 1996; 271: 27744-27750
        • Alvarez Garcia B.
        • Ruiz C.
        • Chacon P.
        • Sabin J.A.
        • Matas M.
        High-sensitivity C-reactive protein in high-grade carotid stenosis: risk marker for unstable carotid plaque.
        J Vasc Surg. 2003; 38: 1018-1024
        • Jouve R.
        • Rolland P.H.
        • Delboy C.
        • Mercier C.
        Thromboxane B2, 6-keto-PGF1 alpha, PGE2, PGF2 alpha, and PGA1 plasma levels in arteriosclerosis obliterans: relationship to clinical manifestations, risk factors, and arterial pathoanatomy.
        Am Heart J. 1984; 107: 45-52
        • Beloqui O.
        • Paramo J.A.
        • Orbe J.
        • et al.
        Monocyte cyclooxygenase-2 overactivity: a new marker of subclinical atherosclerosis in asymptomatic subjects with cardiovascular risk factors?.
        Eur Heart J. 2005; 26: 153-158
        • Cipollone F.
        • Fazia M.
        • Iezzi A.
        • et al.
        Balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1259-1265
        • Takayama K.
        • Garcia-Cardena G.
        • Sukhova G.K.
        • et al.
        Prostaglandin E2 supresses chemokine production in human macrophages trough the EP-4 receptor.
        J Biol Chem. 2002; 277: 44147-44154
        • Bayston T.
        • Ramessur S.
        • Reise J.
        • Jones K.G.
        • Powell J.T.
        Prostaglandin E2 receptors in abdominal aortic aneurysm and human aortic smooth muscle cells.
        J Vasc Surg. 2003; 38: 354-359
        • Zeng Li
        • An S.
        • Goetzl E.J.
        EP4/EP2 receptor-specific prostaglandin E2 regulation of interleukin-6 generation by human HSB.2 early T cells.
        J Pharmacol Exp Ther. 1998; 286: 1420-1426
        • Johnson J.L.
        • Jackson C.L.
        • Angelini G.D.
        • George S.J.
        Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1707-1715
        • Bombardier C.
        • Laine L.
        • Reicin A.
        • et al.
        • VIGOR Study Group
        Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.
        N Engl J Med. 2000; 343: 1520-1528
        • Muckherjee D.
        • Nissen S.E.
        • Topol E.J.
        Risk of cardiovascular events associated with selective COX-2 inhibitors.
        JAMA. 2001; 286: 954-959
        • Rott D.
        • Zhu J.
        • Burnett M.S.
        • et al.
        Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice.
        J Am Coll Cardiol. 2003; 41: 1812-1819
        • Pratico D.
        • Tillmann C.
        • Zhang Z.B.
        • Li H.
        • FitzGerald G.A.
        Acceleration of atherogenesis by COX-1- dependent prostanoid formation in low density lipoprotein receptor knockout mice.
        Proc Natl Acad Sci USA. 2001; 98: 3358-3363
        • Bresalier R.S.
        • Sandler R.S.
        • Quan H.
        • et al.
        Cardiovascular events associated with Rofecoxib in a colorectal adenoma chemoprevention trial.
        N Engl J Med. 2005; 352: 1092-1102
        • Solomon S.D.
        • McMurray J.J.
        • Pfeffer M.A.
        • et al.
        Cardiovascular risk associated with Celecoxib in a clinical trial for colorectal adenoma prevention.
        N Engl J Med. 2005; 352: 1071-1080
        • Burleigh M.E.
        • Babaev V.R.
        • Oates J.A.
        • et al.
        Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice.
        Circulation. 2002; 105: 1816-1823
        • Silverstein F.E.
        • Faich G.
        • Goldstein J.L.
        • et al.
        Gastrointestinal toxicity with celecoxib vs. nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis safety study et al.
        JAMA. 2000; 284: 1247-1255
        • Chenevard R.
        • Hurlimann D.
        • Bechir M.
        • et al.
        Selective COX-2 inhibition improves endothelial function in coronary artery disease.
        Circulation. 2003; 107: 405-409
        • Altman R.
        • Luciardi H.L.
        • Muntaner J.
        • et al.
        Efficacy assessment of meloxicam, a preferential cyclooxygenase-2 inhibitor, in acute coronary syndromes without ST-segment elevation: the nonsteroidal anti-inflammatory drugs in unstable angina treatment-2 (NUT-2) pilot study.
        Circulation. 2002; 106: 191-195
        • Chen F.
        • Eriksson P.
        • Hansson G.K.
        • et al.
        Expression of matrix metalloproteinase 9 and its regulators in the unstable coronary atherosclerotic plaque.
        Int J Mol Med. 2005; 15: 57-65
        • Kai H.
        • Ikeda H.
        • Yasukawa H.
        • et al.
        Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes.
        J Am Coll Cardiol. 1998; 32: 368-372
        • Hernandez-Presa M.A.
        • Martin-Ventura J.L.
        • Ortego M.
        • et al.
        Atorvastatin reduces the expresion of cyclooxygenase in a rabbit model atherosclerosis and in cultured vascular smooth muscle cells.
        Atherosclerosis. 2002; 160: 49-58
        • Cipollone F.
        • Fazia M.
        • Iezzi A.
        • et al.
        Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin- dependent plaque stabilization in humans.
        Circulation. 2003; 107: 1479-1485
        • Cipollone F.
        • Fazia M.
        • Iezzi A.
        • et al.
        Blockade of the angiotensin II type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity.
        Circulation. 2004; 109: 1482-1488