Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice.
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.
Rott
David
D
Cardiovascular Research Institute, Medstar Research Institute, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010, USA.
Zhu
Jianhui
J
Burnett
Mary Susan
MS
Zhou
Yi Fu
YF
Zalles-Ganley
Alexandra
A
Ogunmakinwa
Jibike
J
Epstein
Stephen E
SE
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
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