title: Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice.
abstract: OBJECTIVE
  We examined whether selective cyclooxygenase-2 (COX-2) inhibition in apolipoprotein-E (apoE) deficient mice reduces cytomegalovirus (CMV) replication, and determined whether COX-2 anti-inflammatory activity leads to decreased atherosclerosis.
  
  
  BACKGROUND
  Evidence suggests that CMV infection contributes to atherosclerosis and that this occurs in part through inflammatory mechanisms. Cyclooxygenase-2 inhibitors are potent anti-inflammatory agents. They also inhibit CMV replication in vitro.
  
  
  METHODS
  The apoE deficient mice were either treated or not treated with a selective COX-2 inhibitor, and either infected or not infected with CMV. Viral deoxyribonucleic acid load in salivary glands was determined by quantitative polymerase chain reaction. Atherosclerotic lesion analysis was performed by standard methods.
  
  
  RESULTS
  In vivo COX-2 inhibition, unexpectedly increased viral load: in the CMV-infected animals viral load was 2.58 +/- 1.0 in the nontreated group, 4.74 +/- 1.38 in the group treated with 12 mg/kg/day MF-tricyclic, and 6.51 +/- 1.64 in the group treated with 24 mg/kg/day MF-tricyclic (p trend = 0.050). This increased viral load was paralleled by increased anti-CMV antibody titers. Most surprisingly, COX-2 inhibition significantly increased early atherosclerotic lesion area, independent of viral infection.
  
  
  CONCLUSIONS
  Our study demonstrates that selective inhibition of COX-2 in vivo increases viral load. The finding that inhibition of COX-2 increases atherosclerosis development in apoE deficient mice suggests, unexpectedly, that this enzyme exerts antiatherosclerosis activity, at least in this model.
authors.affiliation: Cardiovascular Research Institute, Medstar Research Institute, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rott
authors.forename: Jianhui
authors.initials: J
authors.lastname: Zhu
authors.forename: Mary Susan
authors.initials: MS
authors.lastname: Burnett
authors.forename: Yi Fu
authors.initials: YF
authors.lastname: Zhou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zalles-Ganley
authors.forename: Jibike
authors.initials: J
authors.lastname: Ogunmakinwa
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D003587:Cytomegalovirus / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology; D004279:DNA, Viral / Q000032:analysis; D018450:Disease Progression; D004198:Disease Susceptibility; D004306:Dose-Response Relationship, Immunologic; D005663:Furans / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000032:analysis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D019562:Viral Load; D014779:Virus Replication
chemical_list: D000914:Antibodies, Viral; D001057:Apolipoproteins E; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D004279:DNA, Viral; D005663:Furans; D007074:Immunoglobulin G; D007527:Isoenzymes; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases