Attenuation of diet‐induced atherosclerosis in rabbits with a highly selective 15‐lipoxygenase inhibitor lacking significant antioxidant properties

British Journal of Pharmacology - Tập 120 Số 7 - Trang 1199-1206 - 1997
Sandra M. Sendobry1, Joseph A. Cornicelli2, Kathryn Welch2, Thomas Bocan2, Bradley D. Tait3, Bharat K. Trivedi3, Norman L. Colbry3, Richard D. Dyer4, Steven J. Feinmark5, Alan Daugherty6,1
1Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
2Department of Artherosclerosis Therapeutics, Parke-Davis, Ann Arbor MI 48105
3Department of Chemistry, Parke-Davis, Ann Arbor MI 48105
4Department of Biochemistry, Parke-Davis, Ann Arbor MI 48105
5Department of Pharmacology, Columbia University, New York, NY 10032 U.S.A.
6Cardiovascular Division, Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis MO 63110

Tóm tắt

15‐Lipoxygenase (15‐LO) has been implicated in the pathogenesis of atherosclerosis because of its localization in lesions and the many biological activities exhibited by its products. To provide further evidence for a role of 15‐LO, the effects of PD 146176 on the development of atherosclerosis in cholesterol‐fed rabbits were assessed. This novel drug is a specific inhibitor of the enzyme in vitro and lacks significant non specific antioxidant properties. PD 146176 inhibited rabbit reticulocyte 15‐LO through a mixed noncompetitive mode with a Ki of 197 nm. The drug had minimal effects on either copper or 2,2′‐azobis(2‐amidinopropane)hydrochloride (ABAP) induced oxidation of LDL except at concentrations 2 orders higher than the Ki. Control New Zealand rabbits were fed a high‐fat diet containing 0.25% wt./wt. cholesterol; treated animals received inhibitor in this diet (175 mg kg−1, b.i.d.). Plasma concentrations of inhibitor were similar to the estimated Ki (197 nm). During the 12 week study, there were no significant differences in weight gain, haematocrit, plasma total cholesterol concentrations, or distribution of lipoprotein cholesterol. The drug plasma concentrations achieved in vivo did not inhibit low‐density lipoprotein (LDL) oxidation in vitro. Furthermore, LDL isolated from PD 146176‐treated animals was as susceptible as that from controls to oxidation ex vivo by either copper or ABAP. PD 146176 was very effective in suppressing atherogenesis, especially in the aortic arch where lesion coverage diminished from 15±4 to 0% (P<0.02); esterified cholesterol content was reduced from 2.1±0.7 to 0 μg mg−1 (P<0.02) in this region. Immunostainable lipid‐laden macrophages present in aortic intima of control animals were totally absent in the drug‐treated group. Results of these studies are consistent with a role for 15‐LO in atherogenesis. British Journal of Pharmacology (1997) 120, 1199–1206; doi:10.1038/sj.bjp.0701007

Từ khóa


Tài liệu tham khảo

10.1074/jbc.271.3.1329

10.1111/j.1432-1033.1993.tb17755.x

10.1074/jbc.270.10.5191

10.1161/01.ATV.11.1.15

BLIGH E.G., 1959, A rapid method of total lipid extraction and characterization, Can. J. Physiol., 37, 911

10.1016/0014-4827(91)90161-M

10.1073/pnas.84.21.7725

CARTER G.W., 1991, The 5‐lipoxygenase inhibition activity of zileuton, J. Pharmacol. Exp. Ther., 256, 929

10.1016/0076-6879(79)63008-2

10.1073/pnas.89.1.217

10.1161/01.ATV.16.12.1488

10.1161/01.ATV.8.6.768

10.1111/j.1476-5381.1989.tb12635.x

10.1111/j.1476-5381.1991.tb12293.x

10.1172/JCI117342

10.1161/01.ATV.14.12.2017

10.1016/0008-6363(96)88585-3

10.1016/0021-9150(93)90085-9

10.1172/JCI117127

10.1172/JCI118062

FORD‐HUTCHINSON A.W., 1991, Arachidonate 15‐lipoxygenase ‐characteristics and potential biological significance, Eicosanoids, 4, 65

10.1172/JCI117334

10.1016/0090-6980(90)90026-R

10.1126/science.2455346

HANSSON G.K., 1989, Detection of activated T lymphocytes in the human atherosclerotic plaque, Am. J. Pathol., 135, 169

10.1172/JCI117784

10.1016/1050-1738(94)00029-U

10.1172/JCI111609

10.1073/pnas.89.16.7384

ISHIKAWA T.T., 1974, Quantitative analysis of cholesterol in 5 and 20 μl of plasma, J. Lipid Res., 15, 286, 10.1016/S0022-2275(20)36809-7

10.1172/JCI117776

10.1073/pnas.84.16.5928

10.1161/01.ATV.14.8.1386

KUHN H., 1990, Occurrence of lipoxygenase products in membranes of rabbit reticulocytes, J. Biol. Chem., 265, 1454, 10.1016/S0021-9258(19)40037-9

KÜHN H., 1990, Oxygenation of biological membranes by the reticulocyte lipoxygenase, J. Biol. Chem., 265, 18351, 10.1016/S0021-9258(17)44759-4

KÜHN H., 1994, Oxidative modification of human lipoproteins by lipoxygenases of different positional specificities, J. Lipid Res., 35, 1749, 10.1016/S0022-2275(20)39770-4

10.1084/jem.179.6.1903

LYNCH S.M., 1993, Mechanisms of copper‐dependent and iron‐dependent oxidative modification of human low density lipoprotein, J. Lipid Res., 34, 1745, 10.1016/S0022-2275(20)35737-0

MCNALLY A.K., 1990, Activated human monocytes oxidize low density lipoprotein by a lipoxygenase dependent pathway, J. Immunol., 145, 254, 10.4049/jimmunol.145.1.254

MOREL D.W., 1994, Treatment of cholesterol‐fed rabbits with dietary vitamins E and C inhibits lipoprotein oxidation but not development of atherosclerosis, J. Nutr., 124, 2123, 10.1093/jn/124.11.2123

10.1073/pnas.86.4.1372

10.1073/pnas.86.3.1046

10.1021/jo00065a013

10.1016/S0022-2275(20)42068-1

10.1161/01.ATV.10.3.336

SEGEL I.H., 1975, Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady State Enzyme Systems, 170

SETTY B.N., 1987, Mitogenic effect of 15‐ and 12‐hydroxyeicosatetraenoic acid on endothelial cells may be mediated via diacylglycerol kinase inhibition, J. Biol. Chem., 262, 17613, 10.1016/S0021-9258(18)45425-7

10.1016/0021-9150(89)90204-9

10.1016/0049-3848(89)90433-7

10.1016/S0006-291X(05)80063-4

SPARROW C.P., 1988, Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell‐mediated oxidative modification, J. Lipid Res., 29, 745, 10.1016/S0022-2275(20)38493-5

10.1172/JCI115793

10.1073/pnas.89.1.128

STEINBERG D., 1989, Beyond cholesterol. Modifications of low density lipoprotein that increase its atherogenicity, N. Engl. J. Med., 320, 915

10.1172/JCI114271

10.1073/pnas.87.18.6959

10.1172/JCI115111

10.1172/JCI117971

Thông tin
Thông tin xuất bản

British Journal of Pharmacology

Tập 120 Số 7

1199-1206

Thông tin tác giả