Proatherogenic and Antiatherogenic Effects of Probucol and Phytosterols in Apolipoprotein E–Deficient Mice

Abstract

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 (rϭ0.69) with the lesion area. HDL cholesterol was reduced (Ͼ75%) 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 (PϽ0.05). 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.

Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E–Deficient Mice

“…Previous studies have reported that probucol enhances lesion formation in the aortic root of female and male apoEϪ/Ϫ mice fed normal chow. 25,26 Consistent with that finding, lesions at this site were larger in probucol than control male mice fed a high-fat chow (Table I), although this difference did not reach statistical significance. Lesion size in the aortic root varied in the probucol group (Table I) owing to 2 animals with no lesions at all (not shown), whereas all other drug-treated animals had larger lesions than the largest individual control mouse.…”

“…Lesion size in the aortic root varied in the probucol group (Table I) owing to 2 animals with no lesions at all (not shown), whereas all other drug-treated animals had larger lesions than the largest individual control mouse. Table I also shows that not only was the reported previously lesion-enhancing effect of probucol 25,26 confined to the aortic root region but also that probucol changed to become increasingly more antiatherogenic the more distal the site examined (Table I). At the abdominal aorta, probucol effectively prevented lesion formation.…”

“…20 It is also ineffective in reducing established lesions in mature, LDL receptor-deficient rabbits 21 and nonhuman primates. 14 Furthermore, probucol promotes atherosclerosis in the aortic origin in LDL receptor- [22][23][24] and apolipoprotein E-deficient (apoEϪ/Ϫ) mice 25,26 for reasons presently unknown.…”

A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats

“…At the time of death, both native hearts and graft tissues as well as the kidneys and other tissues were appropriately collected and processed for histological examinations as previously described (30). Serial sections were cut and stained with hematoxylin and eosin and Masson's trichrome (31). The status of graft rejection was scored using the Billingham rejection grading system (47), including 0 (no rejection) to 3 (severe rejection).…”

Inibição do estresse oxidativo em macrófagos previne a redução no conteúdo do receptor ABCA-1 induzida por albumina modificada por glicação avançada

“…O probucol é um potente antioxidante, capaz de reduzir a oxidação e internalização de LDL na íntima arterial, embora apresente incovenientes sobre o perfil lipídico (Moghadasian et al 1999;Bird et al 1998).…”