Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice
Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice
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DOI：
10.1111/j.1365-2362.2006.01606.x
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发表时间：
2006-03-01
影响因子：
5.5
通讯作者：
Korbut, R
中科院分区：
文献类型：
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作者：
Jawien, J;Gajda, M;Korbut, R
最近的报告指出，在动脉粥样硬化的重要作用，白三烯。白三烯是由5-脂氧合酶与5-脂氧合酶激活蛋白（FLAP）协同作用产生的。我们假设MK-886（一种FLAP抑制剂）可以在致动脉粥样硬化的载脂蛋白E/低密度脂蛋白受体（apoE/LDLR）双敲除（DKO）小鼠模型中减轻动脉粥样硬化的发展。实验组（n = 10）接受与对照组（n = 10）相同的饮食，但与MK-886（Merck，Rahway，NJ）混合，剂量为4 μ g/100 mg体重/天。在6月龄时，在麻醉下处死小鼠。通过正面法测量，对照组中的睾丸病变所占面积百分比为25.15 +/-2.9%，而MK-886给药组为11.16 +/- 0.7%（P < 0.05）。对照组主动脉根部横截面测量的病变面积为455 494 +/- 29 564 μ m（2），MK-886给药组为263 042 +/- 20 736 μ m（2）（P < 0.05）。与对照小鼠相比，MK-886未改变血浆胆固醇脂蛋白谱。最后，我们发现MK-886可能通过减少巨噬细胞含量以及增加胶原和平滑肌细胞含量来增加斑块稳定性。我们的研究结果首次表明MK-886抑制FLAP可减少基因靶向apoE/LDLR-DKO小鼠动脉粥样硬化的发展。
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.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 mu g per 100 mg of body-weight per day. At age 6 months the mice were sacrificed under anaesthesia.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 mu m(2) in the control group versus 263 042 +/- 20 736 mu m(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.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.