(Circulation. 1999;99:1733-1739.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Proatherogenic and Antiatherogenic Effects of Probucol and Phytosterols in Apolipoprotein E–Deficient Mice
Possible Mechanisms of Action
From the Atherosclerosis Specialty Laboratory (M.H.M., J.J.F.) and Cardiovascular Research Laboratory (B.M.M.), Department of Pathology and Laboratory Medicine, Department of Pharmacology and Therapeutics (D.V.G.), Faculty of Pharmaceutical Sciences (B.R.), University of British Columbia and St. Paul's Hospital, Vancouver, Canada.
Correspondence to Jiri J. Frohlich, MD, #180-1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6. E-mail jifr{at}unixg.ubc.ca
Background—The effects of probucol and a phytosterol mixture (FCP-3PI) on atherosclerotic lesion formation, plasma lipoproteins, hepatic and lipoprotein lipase activities, antioxidant enzyme activities, and plasma fibrinogen were investigated in apolipoprotein E–knockout (apoE-KO) mice.
Methods and Results—Three groups of 8 mice were fed a diet containing 9% (wt/wt) fat (controls) or the foregoing diet supplemented with either 1% (wt/wt) probucol (the probucol group) or 2% (wt/wt) FCP-3PI (the FCP-3PI group) for 20 weeks. Compared with controls, atherosclerotic lesion size was 3 times greater in the probucol group, whereas it was decreased by half in the FCP-3PI group. Probucol treatment resulted in high plasma probucol concentrations, which correlated (r=0.69) with the lesion area. HDL cholesterol was reduced (>75%) in the probucol group and slightly increased (14%) in the FCP-3PI–treated group. Postheparin lipoprotein lipase (LPL) activity was significantly reduced in both treatment groups, but only FCP-3PI significantly decreased hepatic lipase activity. Plasma fibrinogen was increased 42% by probucol and decreased 19% by FCP-3PI relative to controls. Probucol significantly increased plasma glutathione reductase, glutathione peroxidase, and superoxide dismutase activities (P<0.05). In contrast to findings in apoE-KO mice, there was no probucol-induced atherosclerosis in their wild-type counterparts fed the same dose for the same period of time.
Conclusions—Antiatherogenic activity of FCP-3PI in apoE-KO mice is associated with an increase in HDL cholesterol concentration along with decreases in hepatic lipase activity and plasma fibrinogen concentrations. Proatherogenic effects of probucol may be related to increased plasma fibrinogen, decreased HDL cholesterol concentrations along with decreased LPL activity, or its direct "toxicity" due to very high plasma concentration. Our studies demonstrate that the antioxidant and cholesterol-lowering properties of probucol do not prevent atherogenesis in this particular animal model.
Key Words: hypercholesterolemia • atherosclerosis • lipoproteins • fibrinogen • antioxidants
This article has been cited by other articles:
 |
|
 |
|
  S. Helske, T. Miettinen, H. Gylling, M. Mayranpaa, J. Lommi, H. Turto, K. Werkkala, M. Kupari, and P. T. Kovanen Accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves J. Lipid Res., July 1, 2008; 49(7): 1511 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Weingartner, D. Lutjohann, S. Ji, N. Weisshoff, F. List, T. Sudhop, K. von Bergmann, K. Gertz, J. Konig, H.-J. Schafers, et al. Vascular effects of diet supplementation with plant sterols. J. Am. Coll. Cardiol., April 22, 2008; 51(16): 1553 - 1561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Othman, M. Suh, G. Fischer, N. Azordegan, N. Riediger, K. Le, D. S. Jassal, and M. H. Moghadasian A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1452 - H1458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Chen, L. Steinhauer, J. Hammerlindl, W. Keller, and J. Zou Biosynthesis of Phytosterol Esters: Identification of a Sterol O-Acyltransferase in Arabidopsis Plant Physiology, November 1, 2007; 145(3): 974 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Wu, N. Di Girolamo, K. Beck, C. G. Hanratty, K. Choy, J. Y. Hou, M. R. Ward, and R. Stocker Probucol [4,4'-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 477 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Nashed, B. Yeganeh, K. T. HayGlass, and M. H. Moghadasian Antiatherogenic Effects of Dietary Plant Sterols Are Associated with Inhibition of Proinflammatory Cytokine Production in Apo E-KO Mice J. Nutr., October 1, 2005; 135(10): 2438 - 2444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Wilund, L. Yu, F. Xu, G. L. Vega, S. M. Grundy, J. C. Cohen, and H. H. Hobbs No Association Between Plasma Levels of Plant Sterols and Atherosclerosis in Mice and Men Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2326 - 2332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Clifton, M. Noakes, D. Ross, A. Fassoulakis, M. Cehun, and P. Nestel High dietary intake of phytosterol esters decreases carotenoids and increases plasma plant sterol levels with no additional cholesterol lowering J. Lipid Res., August 1, 2004; 45(8): 1493 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Waddington, I. B Puddey, and K. D Croft Red wine polyphenolic compounds inhibit atherosclerosis in apolipoprotein E-deficient mice independently of effects on lipid peroxidation Am. J. Clinical Nutrition, January 1, 2004; 79(1): 54 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Li, E. W. Lee, H. Ji, and Z. Zukowska Neuropeptide Y-Induced Acceleration of Postangioplasty Occlusion of Rat Carotid Artery Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1204 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Sundell, P. K. Somers, C. Q. Meng, L. K. Hoong, K.-L. Suen, R. R. Hill, L. K. Landers, A. Chapman, D. Butteiger, M. Jones, et al. AGI-1067: A Multifunctional Phenolic Antioxidant, Lipid Modulator, Anti-Inflammatory and Antiatherosclerotic Agent J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1116 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gervais, S. Pons, A. Nicoletti, C. Cosson, J.-F. Giudicelli, and C. Richer Fluvastatin Prevents Renal Dysfunction and Vascular NO Deficit in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 183 - 189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Bentzon, G. Pasterkamp, and E. Falk Expansive Remodeling Is a Response of the Plaque-Related Vessel Wall in Aortic Roots of ApoE-Deficient Mice: An Experiment of Nature Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 257 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Violi, F. Micheletta, and L. Iuliano Antioxidants and atherosclerosis Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B17 - B21. [Abstract] [PDF]
|
|
|
|
 |
|
 M. H. MOGHADASIAN, B. M. McMANUS, L. B. NGUYEN, S. SHEFER, M. NADJI, D. V. GODIN, T. J. GREEN, J. HILL, Y. YANG, C. H. SCUDAMORE, et al. Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans FASEB J, December 1, 2001; 15(14): 2623 - 2630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Witting, K. Pettersson, J. Letters, and R. Stocker Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20 (8): e26 - e33. [Abstract] [Full Text] [PDF]
|
|