Myeloid Cell 5-Lipoxygenase Activating Protein Modulates the Response to Vascular Injury
Rationale: Human genetics have implicated the 5- lipoxygenase (5-LO) enzyme in the pathogenesis of cardiovascular disease and an inhibitor of the 5-LO activating protein (FLAP) is in clinical development for asthma.
Objective: Here we determined whether FLAP deletion modifies the response to vascular injury.
Methods and Results: Vascular remodeling was characterized 4 weeks after femoral arterial injury in FLAP knockout (FLAP KO) mice and wild type (WT) controls. Both neointimal hyperplasia and the intima / media ratio of the injured artery were significantly reduced in the FLAP KOs while endothelial integrity was preserved. Lesional myeloid cells were depleted and vascular smooth muscle cell (VSMC) proliferation, as reflected by bromodeoxyuridine (BrdU) incorporation, was markedly attenuated by FLAP deletion. Inflammatory cytokine release from FLAP KO macrophages was depressed and their restricted ability to induce VSMC migration ex vivo was rescued with leukotriene B4 (LTB4). FLAP deletion restrained injury and attenuated upregulation of the extracellular matrix protein, tenascin C (TNC), which affords a scaffold for VSMC migration. Correspondingly, the phenotypic modulation of VSMC to a more synthetic phenotype, reflected by morphological change, loss of α-smooth muscle cell actin and upregulation of vascular cell adhesion molecule (VCAM) -1 was also suppressed in FLAP KO mice. Transplantation of FLAP replete myeloid cells rescued the proliferative response to vascular injury.
Conclusions: Expression of lesional FLAP in myeloid cells promotes LTB4 dependent VSMC phenotypic modulation, intimal migration and proliferation.
- vascular injury
- smooth muscle cell
- animal model of human disease remodeling
- angioplasty and stenting
- Received July 19, 2012.
- Revision received December 12, 2012.
- Accepted December 17, 2012.
- Copyright © 2012, Circulation Research