Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibitincreased lipoprotein oxidation and atherosclerosis

Serum paraoxonase (PON1), present on high density lipoprotein, may inhibit low density lipoprotein (LDL) oxidation and protect against atherosclerosis . We generated combined PON1 knockout (KO)/apolipoprotein E (apoE) KO and a poE KO control mice to compare atherogenesis and lipoprotein oxidation. Ear ly lesions were examined in 3-month-old mice fed a chow diet, and advanced lesions were examined in 6-month-old mice fed a high fat diet. In both case s, the PON1 KO/apoE KO mice exhibited significantly more atherosclerosis (5 0-71% increase) than controls. We examined LDL oxidation and clearance in v ivo by injecting human LDL into the mice and following its turnover. LDL cl earance was faster in the double KO mice as compared with controls. There w as a greater rate of accumulation of oxidized phospholipid epitopes and a g reater accumulation of LDL-immunoglobulin complexes in the double KO mice t han in controls. Furthermore, the amounts of three bioactive oxidized phosp holipids were elevated in the endogenous intermediate density lipoprotein/L DL of double KO mice as compared with the controls. Finally, the expression of heme oxygenase-1, peroxisome proliferator-activated receptor gamma, and oxidized LDL receptors were elevated in the livers of double KO mice as co mpared with the controls. These data demonstrate that PON1 deficiency promo tes LDL oxidation and atherogenesis in apoE KO mice.