During the past 15 years, epidemiological,1,2 basic
biological,3- 5 and
experimental studies on atherosclerosis have supported the hypothesis that
antioxidants protect against atherosclerosis6- 8 by
limiting low-density lipoprotein oxidation in the arterial wall. This mechanism
inhibits the pathological accumulation of cholesteryl ester in plaque via
the macrophage scavenger receptor, a process that can cause plaque rupture
and cardiovascular events.9,10 Similarly,
biological mechanisms have been identified in carcinogenesis that may be blocked
by antioxidants.11- 14 In
the past decade, a number of prospective, randomized, placebo-controlled,
3- to 6-year clinical trials have been published, testing the effect of vitamin
E and other antioxidant vitamins or their combinations on clinical manifestations
of cardiovascular disease and cancer.15- 21 These
trials have surprisingly yet consistently shown that commonly used antioxidant
vitamin regimens (vitamins E, C, beta carotene, or a combination) do not significantly
reduce overall cardiovascular events or cancer.
The nuclear receptor heterodimer RXR-LXR modulates the expression of
key gene products (apolipoproteins, transporters, or enzymes) affecting lipid
metabolism, via an upstream hormone response element DR4. RXR is activated
by 9-cis retinoic acid and LXR by certain nuclear oxysterols.34 By affecting these sites of gene regulation, antioxidants
could alter lipoprotein metabolism and lipid levels as has been observed.21 For example, isomers of vitamin A (retinoic acid),
the breakdown product of beta carotene, could interfere with binding of the
specific activator 9-cis retinoic acid to RXR; and antioxidants,
including vitamin E, might alter oxysterol levels or their interaction with
the LXR nuclear receptor by as yet unproven mechanisms. RXR indicates retinoid
x receptor; LXR, liver x receptor; DR, direct repeat; Apo, apolipoprotein;
ABC, ATP-binding cassette transmembrane protein; CETP, cholesterol ester transfer
protein; SREBP, sterol regulatory element-binding protein.
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