REDUCED PROGRESSION OF ATHEROSCLEROSIS IN APOLIPOPROTEIN E-DEFICIENT MICE FOLLOWING CONSUMPTION OF RED WINE, OR ITS POLYPHENOLS QUERCETIN OR CATECHIN, IS ASSOCIATED WITH REDUCED SUSCEPTIBILITY OF LDL TO OXIDATION AND AGGREGATION

The effect of consuming red wine, or its major polyphenol constituents catechin or quercetin, on the development of atherosclerotic lesions, in relation to the susceptibility of plasma LDL to oxidation and to a ggregation, was studied in atherosclerotic apolipoprotein E deficient (E degrees) mice. Forty E degrees mice al the age of 4 weeks were divi ded into four groups, 10 mice in each group, and were supplemented for up to 6 weeks in their drinking water with placebo (1.1% alcohol); ca techin or quercetin (50 mu g/d per mouse), or red wine (0.5 mL/d per m ouse). Consumption of catechin, quercetin, or red wine had no effect o n plasma LDL or HDL cholesterol levels. The atherosclerotic lesion are a was smaller in the treated mice by 39%, 46%, and 48%, respectively, in comparison with E degrees mice that were treated with placebo. In a ccordance with these findings, cellular uptake of LDL derived after ca techin, quercetin, or red wine consumption was found to be reduced by 31%, 40%, and 52%, respectively. These results were associated with re duced susceptibility to oxidation (induced by different modes such as copper ions, free radical generator, or macrophages) of LDL isolated a fter red wine or quercetin and, to a lesser extent after catechin cons umption, in comparison with LDL isolated from the placebo group. Simil ar results were obtained when LDL was preincubated in vitro with red w ine or with the polyphenols prior to its oxidation. Even in the basal oxidative state (not induced oxidation), LDL isolated from E degrees m ice that consumed catechin, quercetin, or red wine for 2 weeks was fou nd to be less oxidized in comparison with LDL isolated from E degrees mice that received placebo, as evidenced by 39%, 48%, and 49% reduced content of LDL-associated lipid peroxides, respectively. This effect c ould be related to enhanced serum paraoxonase activity in the polyphen ol-treated mice. LDL oxidation was previously shown to lead to its agg regation. The present study demonstrated that the susceptibility of LD L to aggregation was reduced in comparison with placebo-treated mice, by 63%, 48%, or 50% by catechin, quercetin, and red wine consumption, respectively, and this effect could be shown also in vitro. The inhibi tion of LDL oxidation by polyphenols could be related, at least in par t, to a direct effect of the polyphenols on the LDL, since both querce tin and catechin were found to bind to the LDL particle via the format ion of an ether bend. We thus conclude that dietary consumption by E d egrees mice of red wine or its polyphenolic flavonoids quercetin and, to a lesser extent, catechin leads to attenuation in the development o f the atherosclerotic lesion, and this effect is associated with reduc ed susceptibility of their LDL to oxidation and aggregation.