Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development

Paraoxonases PON1 and PON3, which are both associated in serum with HDL, protect the serum lipids from oxidation, probably as a result of their ability to hydrolyze specific oxidized lipids. The activity of HDL-associated PONI seems to involve an activity (phospholipase A(2)-like activity, peroxidase-like activity, lactonase activity) which produces LPC. To study the possible role of PONI in macrophage foam cell formation and atherogenesis we used macrophages from control mice, from PONI knockout mice, and from PONI transgenic, mice. Furthermore, we analyzed PON1-treated macrophages and PON1-transfected cells to demonstrate the contribution of PONI to the attenuation of macrophage cholesterol and oxidized lipid accumulation and foam cell formation. PONI was shown to inhibit cholesterol influx [by reducing the formation of oxidized LDL (Ox-LDL), increasing the breakdown of specific oxidized lipids in Ox-LDL, and decreasing macrophage uptake of Ox-LDL]. PONI also inhibits cholesterol biosynthesis and stimulates HDL-mediated cholesterol efflux from macrophages. PON2 and PON3 protect against oxidative stress, with PON2 acting mainly at the cellular level. Whereas serum PONI and PON3 were inactivated under oxidative stress, macrophage PON2 expression and activity were increased under oxidative stress, probably as a compensatory mechanism against oxidative stress. Intervention to increase the paraoxonases (cellular and humoral) by dietary or pharmacological means can reduce macropbage foam cell formation and attenuate atherosclerosis development. (C) 2004 Elsevier Inc. All rights reserved.