Human serum paraoxonase (PON1), an HDL-associated esterase, protects lipoproteins against oxidation, probably by hydrolyzing specific lipid peroxides. As arterial macrophages play a key role in oxidative stress in early atherogenesis, the aim of the present study was to examine the effect of PON1 on macrophage oxidative stress. For this purpose, we used mouse arterial and peritoneal macrophages (MPM) that were collected from two populations of PON1 knockout (KO) mice: one on the genetic background of C57BL / 6J (PON1 (0)) and the other on the background. genetic. of apolipoprotein E KO (PON1 (0) / E (0)). Serum and LDL lipid peroxidation, but not HDL, increased in PON1 (0), compared to C57BL / 6J mice, by 84% and 220%, respectively. Increased oxidative stress was shown in arterial and peritoneal macrophages derived from PON1 (0) or PON1 (0) / E (0) mice, compared to their appropriate controls.
The oxidative stress of macrophages was expressed by a higher content of lipid peroxides in MPM of PON1 (0) and PON1 (0) / E (0) mice by 48% and 80%, respectively, and by a decrease of reduced glutathione (GSH) content, compared to appropriate controls. Furthermore, an increased ability of MPM from PON1 (0) and PON1 (0) / E (0) mice were observed to oxidize LDL (by 40% and 19%, respectively) and to release superoxide anions. In accordance with these results, MPM PON1 (0) mice exhibited 130% more translocation of the cytosolic p47phox component of NADPH-oxidase to the plasma membrane of macrophages, suggesting a greater activation of NADPH-oxidase of the macrophages in PON1 (0) mice, compared to control. MPM mice.
Increased oxidative stress in PON1-deficient mice was observed despite the presence of the other two members of the PON gene family. PON2 and PON3 activities and mRNA expression were found to be present in MPM from PON1-deficient mice. After incubation of PON1 (0) / E (0) derived macrophages with human PON1 (7.5 arylesterase units/ml), the content of cellular peroxides was reduced by 18%, the release of superoxide anions from macrophages was reduced by 33% and macrophage-mediated oxidation of LDL was reduced by 22%.
Finally, a 42% increase in the area of the atherosclerotic lesion was observed in PON1 (0) / E (0) mice, compared to E (0) mice on a regular chow diet. Therefore, we conclude that PON1 can directly reduce oxidative stress in macrophages and serum and that PON1 deficiency results in increased oxidative stress not only in serum but also in macrophages, a phenomenon that may contribute to Accelerated atherosclerosis shown in patients with PON1 deficiency. mice.
paraoxonase transgenic micellar peroxidation lecithin: cholesterol acyltransferase high-density lipoprotein