International Conference: Paraoxonases - Basic and Clinical Directions of Current Research (1st) Held in Ann Arbor, Michigan on April 22-24, 2004
MICHIGAN UNIV ANN ARBOR
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Human serum paraoxonase PON1 is physically associated with high density lipoprotein HDL and the activity of PON 1 was shown to be inversely associated with the risk for atherosclerosis development which is enhanced under oxidative stress. We thus questioned whether this is related to the ability of PON 1 to protect against lipids peroxidation in lipoproteins and in arterial cells. PON 1 hydrolyzed cholesteryl linoleate hydroperoxides CL-OOH in oxidized LDL, HDL and macrophages and in human and mice atherosclerotic coronary or carotid lesions, yielding in the formation of linoleic acid hydroperoxides L-OOH and linoleic acid hydroxide L-OH. This indicates esterase- and peroxidse-like activities for PON1. The PONlQ isoform was 50 more potent than PON1R in this respect. Using site-directed mutagenesis technique, the PON 1s free sulfhydryl group at cysteine - 284 was found to be the enzyme active site. Macrophage foam cell formation is the hallmark of early atherogenesis and hence we questioned the effect of PON 1 on macrophage atherogenicity. PON 1 hydrolyzed macrophage lipid peroxides PD resulting in a 40 decreased content of PD, which was associated with a 36 reduced macrophage mediated oxidation of LDL and also in a 44 decreased cellular uptake of oxidized LDL secondary to a decrease in the expression of the scavenger receptor CD-36. On using PON 1 - deficient mice PON1E, a 42 increased atherosclerotic lesion size was shown in comparison to control E mice and this was associated with increased 40-60 oxidative stress in their serum, as well as in their macrophages peritoneal and arterial. In macrophages from PON 1 mice, NADPH oxidase activation was evident, resulting in enhanced cell- mediated oxidation of LDL. PON 1 action on macrophages reversed cellular oxidative stress toward normal levels.
- Anatomy and Physiology
- Medicine and Medical Research