The oxidation of
apolipoprotein B-containing
lipoproteins and
cell membrane lipids is believed to play an integral role in the development of fatty streak lesions, an initial step in
atherogenesis. We have previously shown that two
antioxidant-like
enzymes,
paraoxonase (PON)-1 and PON3, are
high density lipoprotein-associated
proteins capable of preventing the oxidative modification of
low density lipoprotein (
LDL) (Reddy, S. T., Wadleigh, D. J., Grijalva, V., Ng, C., Hama, S., Gangopadhyay, A., Shih, D. M., Lusis, A. J., Navab, M., and Fogelman, A. M. (2001) Arterioscler. Thromb. Vasc. Biol. 21, 542-547). In the present study, we demonstrate that PON2 (i) is not associated with
high density lipoprotein; (ii) has
antioxidant properties; and (iii) prevents
LDL lipid peroxidation, reverses the oxidation of mildly
oxidized LDL (
MM-LDL), and inhibits the ability of
MM-LDL to induce monocyte chemotaxis. The PON2
protein was overexpressed in HeLa cells using the
tetracycline-inducible ("Tet-On") system, and its
antioxidant capacity was measured in a fluorometric assay. Cells that overexpressed PON2 showed significantly less intracellular oxidative stress following treatment with
hydrogen peroxide or oxidized
phospholipid. Moreover, cells that overexpressed PON2 were also less effective in oxidizing and modifying
LDL and, in fact, were able to reverse the effects of preformed
MM-LDL. Our results suggest that PON2 possesses
antioxidant properties similar to those of PON1 and PON3. However, in contrast to PON1 and PON3, PON2 may exert its
antioxidant functions at the cellular level, joining the host of intracellular
antioxidant enzymes that protect cells from oxidative stress.