title: Cyclooxygenase-2 in endothelial and vascular smooth muscle cells restrains atherogenesis in hyperlipidemic mice.
abstract: BACKGROUND
  Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages.
  
  
  RESULTS
  In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I2 and prostaglandin E2, elevated blood pressure, and accelerated atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, α-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants.
  
  
  CONCLUSIONS
  Although atherogenesis is accelerated in global COX-2 knockouts, consistent with evidence of risk transformation during chronic nonsteroidal anti-inflammatory drug administration, this masks the contrasting effects of enzyme depletion in macrophages versus vascular smooth muscle cells and endothelial cells. Targeting delivery of COX-2 inhibitors to macrophages may conserve their efficacy while limiting cardiovascular risk.
authors: Institute for Translational Medicine and Therapeutics (S.Y.T., J.M., J.L., G.A.F.) and Perelman School of Medicine, Department of Animal Biology, School of Veterinary Medicine (L.T., E.P.), University of Pennsylvania, Philadelphia.
authors: Soon Yew
authors: SY
authors: Tang
authors: James
authors: J
authors: Monslow
authors: Leslie
authors: L
authors: Todd
authors: John
authors: J
authors: Lawson
authors: Ellen
authors: E
authors: Puré
authors: Garret A
authors: GA
authors: FitzGerald
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D001794:Blood Pressure / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D006949:Hyperlipidemias / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics; D012307:Risk Factors
chemical_list: D004041:Dietary Fats; D011973:Receptors, LDL; D011464:Epoprostenol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: atherogenesis; cyclooxygenase; endothelial cell; prostaglandin; vascular smooth muscle