title: Atorvastatin reduces the expression of prostaglandin E2 receptors in human carotid atherosclerotic plaques and monocytic cells: potential implications for plaque stabilization.
abstract: Prostaglandin E2 (PGE2), the product of cyclooxygenase-2 (COX-2) and prostaglandin E synthase-1 (mPGES-1), acts through its receptors (EPs) and induces matrix metalloproteinase (MMP) expression, which may favor the instability of atherosclerotic plaques. The effect of statins on EPs expression has not been previously studied. The aim of this study was to investigate the effect of atorvastatin (ATV, 80 mg/d, for one month) on EP expression in plaques and peripheral blood mononuclear cells (PBMC) of patients with carotid atherosclerosis. In addition, we studied the mechanisms by which statins could modulate EPs expression on cultured monocytic cells (THP-1) stimulated with proinflammatory cytokines (IL-1beta and TNF-alpha). Patients treated with atorvastatin showed reduced EP-1 (14 +/- 1.8% versus 26 +/- 2%; P < 0.01), EP-3 (10 +/- 1.5% versus 26 +/- 1.5%; P < 0.05), and EP-4 expression (10 +/- 4.1% versus 26.6 +/- 4.9%; P < 0.05) in atherosclerotic plaques (immunohistochemistry), and EP-3 and EP-4 mRNA expression in PBMC (real time PCR) in relation to non-treated patients. In cultured monocytic cells, atorvastatin (10 micromol/L) reduced EP-1/-3/-4 expression, along with COX-2, mPGES-1, MMP-9, and PGE2 levels elicited by IL-1beta and TNF-alpha. Similar results were noted with aspirin (100 micromol/L), dexamethasone (1 micromol/L), and the Rho kinase inhibitors Y-27632 and fasudil (10 micromol/L both). The effect of atorvastatin was reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. On the whole, we have shown that atorvastatin reduces EPs expression in atherosclerotic plaques and blood mononuclear cells of patients with carotid stenosis and in cultured monocytic cells. The inhibition of EP receptors could explain, at least in part, some of the mechanisms by which statins could modulate the COX-2/mPGES-1 proinflammatory pathway and favor plaque stabilization in humans.
authors.affiliation: Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Gómez-Hernández
authors.forename: Eva
authors.initials: E
authors.lastname: Sánchez-Galán
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Cristina
authors.initials: C
authors.lastname: Vidal
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Mónica
authors.initials: M
authors.lastname: Ortego
authors.forename: Melina
authors.initials: M
authors.lastname: Vega
authors.forename: Javier
authors.initials: J
authors.lastname: Serrano
authors.forename: Luis
authors.initials: L
authors.lastname: Ortega
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Hernández
authors.forename: José
authors.initials: J
authors.lastname: Tunón
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D000368:Aged; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D000069059:Atorvastatin; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics; D015232:Dinoprostone / Q000032:analysis; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000235:genetics; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D008798:Mevalonic Acid / Q000494:pharmacology; D008875:Middle Aged; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects*; D000071876:Prostaglandin-E Synthases; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D018078:Receptors, Prostaglandin E / Q000032:analysis / Q000187:drug effects*; D020741:rho GTP-Binding Proteins / Q000502:physiology; D054460:rho-Associated Kinases
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011758:Pyrroles; D018078:Receptors, Prostaglandin E; D000069059:Atorvastatin; D051546:Cyclooxygenase 2; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020781:Matrix Metalloproteinase 1; D020741:rho GTP-Binding Proteins; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone; D008798:Mevalonic Acid