Atorvastatin reduces the expression of cyclooxygenase-2 in a rabbit model of atherosclerosis and in cultured vascular smooth muscle cells.
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.
Hernández-Presa
Miguel Angel
MA
Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
Martín-Ventura
José Luis
JL
Ortego
Mónica
M
Gómez-Hernández
Almudena
A
Tuñón
José
J
Hernández-Vargas
Purificación
P
Blanco-Colio
Luis Miguel
LM
Mas
Sebastián
S
Aparicio
César
C
Ortega
Luis
L
Vivanco
Fernando
F
Gerique
Juan Gómez
JG
Díaz
Cristina
C
Hernández
Gonzalo
G
Egido
J
J
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
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