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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 ?-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.

SUBMITTER: Yu Z

PROVIDER: S-EPMC3340044 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice.

Yu Zhou Z Crichton Irene I Tang Soon Yew SY Hui Yiqun Y Ricciotti Emanuela E Levin Mark D MD Lawson John A JA Puré Ellen E FitzGerald Garret A GA

Proceedings of the National Academy of Sciences of the United States of America 20120409 17

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. W ...[more]

PMID: 22493243

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Project description:Rationale: Previous studies have indicated an important role for complement in atherosclerosis, a lipid-driven chronic inflammatory disease associated to oxidative stress in the vessel wall. However, it remains unclear how complement is activated in the process of atherogenesis. An accepted general model for complement activation in the context of ischemia reperfusion injury is that ischemia induces the exposure of neoepitopes that are recognized by natural self-reactive IgM antibodies, and that in turn activate complement. Objective: We investigated whether a similar phenomenon may be involved in the pathogenesis of atherosclerosis, and whether interfering with this activation event, together with inhibition of subsequent amplification of the cascade at the C3 activation step, can provide protection against atherogenesis. Methods and Results: We utilized C2scFv-Crry, a novel construct consisting of a single chain antibody (scFv) linked to Crry, a complement inhibitor that functions at C3 activation. The scFv moiety was derived from C2 IgM mAb that specifically recognizes phospholipid neoepitopes known to be expressed after ischemia. C2scFv-Crry targeted to the atherosclerotic plaque of Apoe -/- mice, demonstrating expression of the C2 neoepitope. C2scFv-Crry administered twice per week significantly attenuated atherosclerotic plaque in the aorta and aortic root of Apoe -/- mice fed with a high-fat diet (HFD) for either 2 or 4 months, and treatment reduced C3 deposition and membrane attack complex formation as compared to vehicle treated mice. C2scFv-Crry also inhibited the uptake of oxidized low-density-lipoprotein (oxLDL) by peritoneal macrophages, which has been shown to play a role in pathogenesis, and C2scFv-Crry-treated mice had decreased lipid content in the lesion with reduced oxLDL levels in serum compared to vehicle-treated mice. Furthermore, C2scFv-Crry reduced the deposition of endogenous total IgM in the plaque, although it did not alter serum IgM levels, further indicating a role for natural IgM in initiating complement activation. Conclusion: Neoepitope targeted complement inhibitors represent a novel therapeutic approach for atherosclerosis.

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Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice.

Publications

Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice.

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