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 microg 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 microm(2) in the control group versus 263,042 +/- 20,736 microm(2) 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.
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 microg 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 microm(2) in the control group versus 263,042 +/- 20,736 microm(2) 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.
Authors: M Mehrabian; F T Schulthess; M Nebohacova; L W Castellani; Z Zhou; J Hartiala; J Oberholzer; A J Lusis; K Maedler; H Allayee Journal: Diabetologia Date: 2008-04-18 Impact factor: 10.122