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.


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.
Jawien
J
J
Jagiellonian University School of Medicine, 31-531 Cracow, Poland. mmjawien@cyf-kr.edu.pl
Gajda
M
M
Rudling
M
M
Mateuszuk
L
L
Olszanecki
R
R
Guzik
T J
TJ
Cichocki
T
T
Chlopicki
S
S
Korbut
R
R
D058927:5-Lipoxygenase-Activating Proteins; D000199:Actins / Q000032:analysis; D000818:Animals; D001011:Aorta / Q000473:pathology; D001018:Aortic Diseases / Q000188:drug therapy; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000032:analysis; D004032:Diet; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles / Q000008:administration & dosage*; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage*; D008264:Macrophages; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000737:chemistry; D014280:Triglycerides / Q000097:blood; D002722:Chlorobenzenes
D058927:5-Lipoxygenase-Activating Proteins; D000199:Actins; D002352:Carrier Proteins; D002784:Cholesterol; D003094:Collagen; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D014280:Triglycerides; C548593:Alox5ap protein, mouse; C060893:MK-886; D002722:Chlorobenzenes