Abstract 1048: Attenuation of Atherosclerosis and Monocyte-Macrophage Inflammation in ApoE-Deficient Mice Treated with the 5-Lipoxygenase Inhibitor VIA-2291
Vascular inflammation has been implicated in all stages of atherosclerosis. Recently, several lines of evidence have suggested an important role for 5-lipoxygenase (5-LO) leukotriene biosynthesis in the inflammatory process during the development and progression of atherosclerosis in humans and mice. Variants of the 5-LO locus have been linked to atherosclerosis susceptibility in human genetic studies and increased 5-LO expression has been demonstrated in advanced human lesions, colocalizing with macrophages in the intima. Abundant expression of 5-LO has been found to colocalize with macrophages in aortic lesions also in mice. In line with this, it has been speculated that blockade of the 5-LO leukotriene pathway may be of therapeutic value in atherosclerosis. In the present study, we have investigated the impact of the 5-LO inhibitor VIA-2291 on atherosclerosis in ApoE-deficient mice. Four week-old ApoE−/− mice were exposed to an atherogenic diet for 20 weeks prior to 4 weeks once daily oral administration of 10 mg/kg VIA-2291, 50 mg/kg VIA-2291 or vehicle (0.9% saline) (n=4/group). En face analysis revealed a dose-dependent decline in the extent of atherosclerosis in mice administered VIA-2291, with a 30% (p<0.001) reduction at 10 mg/kg and a 40% (p<0.001) reduction in mice treated at 50mg/kg VIA-2291, compared to mice receiving vehicle. Cross-sectional analysis of percentage lesion area in the aortic root showed a similar reduction. Immunohistochemistry with a monocyte/macrophage specific antibody (MOMA-2) identified this cell type within all layers of aortic lesions, with a predominant amount being found in the intima. Mice administered 50 mg/kg VIA-2291 displayed 35% (p<0.05) less MOMA-2 reactivity counts/mm2 lesion compared to mice receiving vehicle, indicating a marked effect of VIA-2291 on monocytes/macrophages. In conclusion, treatment with VIA-2291 significantly attenuated the progression of atherosclerosis in the ApoE-deficient mice and exhibited an inhibitory effect on monocytes/macrophages in remaining lesions, suggesting that blockade of the 5-LO leukotriene pathway with VIA-2291 may be of potential therapeutic benefit in atherosclerosis.