Evidence for a paraoxonase-independent inhibition of low-density lipoprotein oxidation by high-density lipoprotein

A Graham, D G Hassall, S Rafique, J S Owen
Atherosclerosis 1997, 135 (2): 193-204
One mechanism by which plasma high-density lipoprotein (HDL) may protect against atherogenesis is by inhibiting the oxidation of low-density lipoprotein (LDL). Recent evidence suggests that paraoxonase, an HDL-associated, calcium-dependent enzyme, may be responsible for the antioxidant action of HDL (Mackness et al., Atherosclerosis 1993;104:129; Mackness et al., FEBS Lett 1991;286:152; Watson et al., J Clin Invest 1995;96:2882; Navab et al., Arterio Thromb Vasc Biol 1996;16:831); in particular, paraoxonase activity inhibits the formation of 'minimally oxidized' LDL by hydrolyzing biologically active oxidized phospholipids (Watson et al., J Clin Invest 1995;96:2882; Navab et al., Arterio Thromb Vasc Biol 1996;16:831). However, antioxidant effects of HDL have also been demonstrated under calcium-free conditions, arguing that this enzyme may not be the only mechanism by which HDL inhibits LDL oxidation (Tribble et al., J Lipid Res 1995;36:2580). Here we have evaluated the role of paraoxonase in prevention of LDL oxidation by using HDL subfractions, isolated from human serum or EDTA-plasma, which display markedly different levels of paraoxonase activity; the abilities of modified forms of HDL to prevent LDL oxidation by cultured human (THP-1) macrophages were also assessed. Paraoxonase activity was substantially lower in HDL prepared from plasma compared to serum HDL; moreover, virtually all of the lipoprotein-associated paraoxonase activity was located in the HDL3 fraction, with HDL2 retaining only 1-5% of the total activity. Despite possessing 5-fold differences in paraoxonase activity, HDL3 isolated from plasma or serum was equally effective in inhibiting LDL oxidation by THP-1 macrophages; furthermore, although plasma HDL3 was more protective than plasma HDL2, the latter did significantly inhibit LDL oxidation. Non-paraoxonase antioxidant constituents of plasma HDL3 were investigated further. ApoHDL3, the totally delipidated form of HDL3, was much less effective than native HDL3; when examined individually, purified apolipoprotein A-II gave greater protection than apo A-I, although this effect was not evident in apo A-II-enriched HDL3. Partial delipidation of HDL3, which removes both neutral lipids and alpha-tocopherol, did not significantly diminish its ability to inhibit LDL oxidation by THP-1 macrophages; phospholipid vesicles prepared from partially delipidated HDL3 also inhibited LDL oxidation effectively. We conclude that, in this model of cellular LDL oxidation, the phospholipid fraction of HDL exerts inhibitory effects which are independent of HDL paraoxonase activity.

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