Abstract 13682: 5-Lipoxygenase Activating Protein Attenuates the Response to Vascular Injury
Background: Inflammation and vascular remodeling are hallmarks of restenosis after angioplasty. 5-lipoxygenase (5-LO), together with 5-lipoxygenase activating protein (FLAP), catalyze the synthesis of leukotrienes (LTs), a group of inflammatory mediators.
Methods and results: We tested the hypothesis that FLAP deficiency would attenuate the response to vascular injury. CD 45+ leucocytes enriched for FLAP expression were markedly increased in neointima at 1, 2 and 3 weeks after vascular injury. Deletion of FLAP significantly reduced both neointimal hyperplasia and vascular stenosis (40.4. ± 6.8 versus 17.2 ± 4.1x 103 pixel area, P< 0.01 and 57.2 ± 10.1% versus 33 ± 5.9%, P<0.05). Vascular smooth muscle cell (VSMC) proliferation and leukocyte infiltration were both decreased in FLAP-/- mice. Induction of tenascin-C, an abundant extracellular matrix protein that affords a facilitatory scaffold for migration and proliferation, was attenuated in FLAP-/- mice. VSMCs changed from a “contractile” to a “synthetic” phenotype after vascular injury, reflected by morphological change, loss of α-smooth muscle cell actin and upregulation of vascular cell adhesion molecule -1 during neointima formation. This transformation was suppressed in FLAP-/- mice. Suppression of macrophage LTB4 and inflammatory cytokines attenuated VSMC migration in vitro, a phenotype rescued by exogenous LTB4, but not by LTD4. VSMCs isolated from FLAP-/- mice were also less responsive to proliferative and migratory stimuli than cells from wild type mice.
Conclusion: Deletion of FLAP in mice attenuates neointimal hyperplasia after vascular injury by reducing local inflammation and regulating VSMC proliferation and migration. This raises for consideration the therapeutic potential of FLAP inhibition as an adjuvant for percutaneous coronary intervention.
- © 2011 by American Heart Association, Inc.