Combined Serum Paraoxonase Knockout/Apolipoprotein E Knockout Mice Exhibit Increased Lipoprotein Oxidation and Atherosclerosis

Abstract

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 apoE KO control mice to compare atherogenesis and lipoprotein oxidation. Early 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 cases, the PON1 KO/apoE KO mice exhibited significantly more atherosclerosis (50 -71% increase) than controls. We examined LDL oxidation and clearance in vivo by injecting human LDL into the mice and following its turnover. LDL clearance was faster in the double KO mice as compared with controls. There was a greater rate of accumulation of oxidized phospholipid epitopes and a greater accumulation of LDL-immunoglobulin complexes in the double KO mice than in controls. Furthermore, the amounts of three bioactive oxidized phospholipids were elevated in the endogenous intermediate density lipoprotein/LDL of double KO mice as compared with the controls. Finally, the expression of heme oxygenase-1, peroxisome proliferator-activated receptor ␥, and oxidized LDL receptors were elevated in the livers of double KO mice as compared with the controls. These data demonstrate that PON1 deficiency promotes LDL oxidation and atherogenesis in apoE KO mice.

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

“…Studies of animal models [5][6][7] and in humans [8,9] are consistent with the hypothesis that PON1 decreases the risk of cardiovascular disease by lowering levels of oxidative stress, notably lipoprotein oxidation. In earlier studies, we proposed that HDL acquires PON1 by desorption from the hepatic cell membrane in a process probably mediated or facilitated by transient anchoring of HDL to the membrane [10].…”

The paraoxonase PON1 promoter polymorphism C(-107)T is associated with increased serum glucose concentrations in non-diabetic patients

“…The increased frequency of low expressor promoter genotypes is interesting in the context of the anti-oxidant function of PON1, protecting in particular serum lipids and lipoproteins from oxidation [36,37]. Lower serum concentrations of PON1 have been associated with increased lipid oxidation, i. e. greater oxidative stress, in animal models [38,39] and human beings [24]. An increased predisposition to oxidative stress could therefore be one consequence of low expressor PON1 genotypes.…”

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

“…Indeed, PON1 protects LDL particles against copper-induced lipid oxidation in vitro [3,28,29] and transgenic mice overexpressing the human PON1 gene have reduced atherosclerotic lesions [48]. Moreover, PON1 knockout mice display accelerated atherosclerosis progression and increased lipid oxidation [40,42,43]. Epidemiological studies indicate that high PON1 activity is inversely associated with the progression of atherosclerosis and reduction in the incidence of coronary artery disease [2,4,25,26,30,33].…”