title: Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice.
abstract: Suppression of cyclooxygenase 2 (COX-2)-derived prostacyclin (PGI(2)) is sufficient to explain most elements of the cardiovascular hazard from nonsteroidal antinflammatory drugs (NSAIDs). However, randomized trials are consistent with the emergence of cardiovascular risk during chronic dosing with NSAIDs. Although deletion of the PGI(2) receptor fosters atherogenesis, the importance of COX-2 during development has constrained the use of conventional knockout (KO) mice to address this question. We developed mice in which COX-2 was deleted postnatally, bypassing cardiorenal defects exhibited by conventional KOs. When crossed into ApoE-deficient hyperlipidemic mice, COX-2 deletion accelerated atherogenesis in both genders, with lesions exhibiting leukocyte infiltration and phenotypic modulation of vascular smooth muscle cells, as reflected by loss of α-smooth muscle cell actin and up-regulation of vascular cell adhesion molecule-1. Stimulated peritoneal macrophages revealed suppression of COX-2-derived prostanoids and augmented 5-lipoxygenase product formation, consistent with COX-2 substrate rediversion. Although deletion of the 5-lipoxygenase activating protein (FLAP) did not influence atherogenesis, it attenuated the proatherogeneic impact of COX-2 deletion in hyperlipidemic mice. Chronic administration of NSAIDs may increasingly confer a cardiovascular hazard on patients at low initial risk. Promotion of atherogenesis by postnatal COX-2 deletion affords a mechanistic explanation for this observation. Coincident inhibition of FLAP may offer an approach to attenuating such a risk from NSAIDs.
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yu
authors.forename: Irene
authors.initials: I
authors.lastname: Crichton
authors.forename: Soon Yew
authors.initials: SY
authors.lastname: Tang
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Hui
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Mark D
authors.initials: MD
authors.lastname: Levin
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013379:Substrate Specificity
chemical_list: D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2