Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice

Background: Recent reports point to an important role of leukotrienes in atherogenesis. Leukotrienes are produced by 5-lipoxygenase co-operating with five lipoxygenase activating protein (FLAP). We hypothesized that MK-886, an inhibitor of FLAP, could attenuate the development of atherosclerosis in the atherogenic apolipoprotein E/low density lipoprotein receptor (apoE/LDLR) double knockout (DKO) mouse model. Materials and methods: Female apoE/LDLR-DKO mice at the age of 8 weeks were put on Western diet. The experimental group (n = 10) received the same diet as the control group (n = 10), but mixed with MK-886 (Merck, Rahway, NJ) at a dose of 4 µg per 100 mg of body-weight per day. At age 6 months the mice were sacrificed under anaesthesia. Results: Measured by the en face method, the percentage of area occupied by lesions in aortas in the control group was 25·15 ± 2·9%, whereas in the MK-886-treated group it was 11·16 ± 0·7% (P < 0·05). Lesion area measured by cross-section of aortic roots was 455 494 ± 29 564 µm2 in the control group versus 263 042 ± 20 736 µm2 in the MK-886-treated group (P < 0·05). The MK-886 did not change the plasma cholesterol lipoprotein profile as compared with the control mice. Finally, we show that MK-886 may increase plaque stability by decreasing the macrophage content as well as increasing the collagen and smooth-muscle cell content. Conclusions: Our results show for the first time that inhibition of FLAP by MK-886 reduces development of atherosclerosis in gene-targeted apoE/LDLR-DKO mice