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

Jawien, J., Gajda, M., Rudling, M., Mateuszuk, L., Olszanecki, R., Guzik, T..J., Cichocki, T., Chlopicki, S. and Korbut, R. (2006) Inhibition of five lipoxygenase activating protein (FLAP) by MK-886 decreases atherosclerosis in apoE/LDLR-double knockout mice. European Journal of Clinical Investigation, 36(3), pp. 141-146. (doi: 10.1111/j.1365-2362.2006.01606.x) (PMID:16506957)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Guzik, Professor Tomasz
Authors: Jawien, J., Gajda, M., Rudling, M., Mateuszuk, L., Olszanecki, R., Guzik, T..J., Cichocki, T., Chlopicki, S., and Korbut, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:European Journal of Clinical Investigation
Publisher:Wiley
ISSN:0014-2972
ISSN (Online):1365-2362
Published Online:27 February 2006

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