Anti-atherogenic effect of BHB-TZD having inhibitory activities on cyclooxygenase and 5-lipoxygenase in hyperlipidemic mice.
Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), which play pivotal roles in atherogenesis, have been reported to be involved in plaque stability. Licofelone, a dual COX and 5-LOX inhibitor, has been reported to possess anti-atherogenic effect in rabbit atherosclerosis model. We therefore investigated the anti-atherogenic effect of BHB-TZD [5-(3,5-di-tert-butyl-4-hydroxybenzylidene)thiazolidin-2,4-dione], a dual COX and 5-LOX inhibitor, in low density lipoprotein receptor null (LDLR-/-) mice. Fifteen LDLR-/- mice were fed a western diet (control group), whereas 15 were fed a western diet plus 0.1% (w/w) BHB-TZD (BHB-TZD group). After 8 weeks, the BHB-TZD group had markedly lower serum levels of leukotriene B(4) and prostaglandin E(2) than the control group. Interestingly, BHB-TZD treatment also reduced plasma triglyceride level without significant changes in total cholesterol and HDL levels. Compared with control mice, BHB-TZD fed mice had 52% fewer fatty streak lesions in the aortic sinus, as well as fewer initial lesions in the aortic arch. Macrophage infiltration into the lesions was 40% lower, and collagen and smooth muscle cells were increased by 102% and 96%, respectively, in the BHB-TZD group compared with the control group. In addition, aortic expression of proatherogenic molecules including TNF-alpha, IL-1beta, IL-6, MCP-1 and VCAM-1, was lower in the BHB-TZD group than the control group. BHB-TZD treatment also reduced MMP-2 and MMP-9 expressions in aorta. In conclusion, BHB-TZD effectively attenuated atherosclerosis in mouse model, suggesting its therapeutic potential for atherosclerosis.
Choi
Jae-Hoon
JH
Laboratory of Cardiovascular Genomics, Division of Molecular Life Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul 120-750, Republic of Korea.
Jeon
Hyung Jun
HJ
Park
Jong-Gil
JG
Sonn
Seong Keun
SK
Lee
Mi-Ran
MR
Lee
Mi-Ni
MN
You
Hye Jin
HJ
Kim
Geun-Young
GY
Kim
Jae-Hong
JH
Lee
Mun Han
MH
Kwon
Oh-Seung
OS
Nam
Ki-Hoan
KH
Kim
Hyoung-Chin
HC
Jeong
Tae-Sook
TS
Lee
Woo Song
WS
Oh
Goo Taeg
GT
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007975:Leukotriene B4 / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
C507175:5-(3,5-di-tert-butyl-4-hydroxybenzylidene)thiazolidine-2,4-dione; D016861:Cyclooxygenase Inhibitors; D018836:Inflammation Mediators; D008075:Lipoproteins, HDL; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; D045162:Thiazolidinediones; D014280:Triglycerides; D007975:Leukotriene B4; D002784:Cholesterol; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone