title: Atorvastatin reduces the expression of cyclooxygenase-2 in a rabbit model of atherosclerosis and in cultured vascular smooth muscle cells.
abstract: Inflammation is involved in the genesis and rupture of atherosclerotic plaques. We assessed the effect of atorvastatin (ATV) on the expression of cyclooxygenase-2 (COX-2) and other proinflammatory molecules in a rabbit model of atherosclerosis. Fourteen animals underwent injury of femoral arteries and 2 weeks of atherogenic diet. Afterwards, they were randomized to receive either 5 mg/kg per day of ATV (n=8) or no treatment (NT, n=6) during 4 weeks, and were finally killed. ATV reduced lipid levels, neointimal size (0.13 (0.03-0.29) mm(2) vs 0.65 (0.14-1.81) mm(2), P=0.005) and the percentage of neointimal area positive for macrophages (1% (0-3) vs 19% (5-32), P=0.001), COX-2 (32% (23-39) vs 60% (37-81) P=0.019), interleukin-8 (IL-8) (23% (3-63) vs 63% (25-88) P=0.015), and metalloproteinase-3 (19% (12-34) vs 42% (27-93), P=0.010), without significant differences in COX-1 expression (immunohistochemistry). In situ hybridization confirmed a decreased expression of COX-2 mRNA (22% (5-40) vs 43% (34-59) P=0.038). The activity of nuclear factor-kappaB, which controls many proinflammatory genes including COX-2, was reduced in atherosclerotic lesions (3538 (2663-5094) vs 8696 (5429-11312)) positive nuclei per mm(2), P=0.001) and circulating mononuclear cells (2966 vs 17130 arbitrary units). In cultured vascular smooth muscle cells, ATV reduced the expression of COX-2 mRNA induced by IL-1beta and TNF-alpha without affecting COX-1 expression. In conclusion, ATV, besides decreasing a number of inflammatory mediators in the atherosclerotic lesion, significantly downregulates COX-2 both in vivo and in vitro. These anti-inflammatory actions could partially account for the reduction of acute coronary events achieved by statins.
authors.affiliation: Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Hernández-Presa
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Mónica
authors.initials: M
authors.lastname: Ortego
authors.forename: Almudena
authors.initials: A
authors.lastname: Gómez-Hernández
authors.forename: José
authors.initials: J
authors.lastname: Tuñón
authors.forename: Purificación
authors.initials: P
authors.lastname: Hernández-Vargas
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Sebastián
authors.initials: S
authors.lastname: Mas
authors.forename: César
authors.initials: C
authors.lastname: Aparicio
authors.forename: Luis
authors.initials: L
authors.lastname: Ortega
authors.forename: Fernando
authors.initials: F
authors.lastname: Vivanco
authors.forename: Juan Gómez
authors.initials: JG
authors.lastname: Gerique
authors.forename: Cristina
authors.initials: C
authors.lastname: Díaz
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Hernández
authors.forename: J
authors.initials: J
authors.lastname: Egido
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy*; D000069059:Atorvastatin; D002478:Cells, Cultured / Q000187:drug effects*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D016209:Interleukin-8 / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis* / Q000187:drug effects*; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000097:blood / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000187:drug effects*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000187:drug effects; D011758:Pyrroles / Q000627:therapeutic use*; D011817:Rabbits; D011897:Random Allocation; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016209:Interleukin-8; D007527:Isoenzymes; D008055:Lipids; D016328:NF-kappa B; D020033:Protein Isoforms; D011758:Pyrroles; D000069059:Atorvastatin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases