Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome.
BACKGROUND
The metabolic syndrome is typified by obesity, dyslipidemia, diabetes, hypertension, increased oxidative stress, and accelerated atherosclerosis. Paraoxonase1 (PON1), a high-density lipoprotein (HDL)-associated antioxidant enzyme that prevents the oxidation of low-density lipoprotein (LDL), is low in the metabolic syndrome.


RESULTS
We used adenovirus-mediated PON1 gene transfer (AdPON1) to overexpress human PON1 in mice with combined leptin and LDL receptor deficiency, a model of metabolic syndrome. PON1 activity, plasma lipids, the titer of autoantibodies against malondialdehyde (MDA)-modified LDL, and atherosclerosis in AdPON1 mice were compared with these in mice that received a control recombinant adenovirus (AdRR5). PON1 activity was increased 4.4-fold (P<0.001) in AdPON1 mice (N = 12), whereas in AdRR5 mice (N = 11) activity did not change. Expressing human PON1 significantly reduced the total plaque volume, the volume of plaque macrophages, and of plaque-associated oxidized LDL. It increased the percentage of smooth muscle cells in the plaques. Expressing human PON1 lowered the titer of autoantibodies against MDA-modified LDL, a proxy for oxidized LDL in mice. It had no overall effect on plasma total cholesterol and triglycerides, as evidenced by the similar area under the curves, and on the HDL distribution profile.


CONCLUSIONS
Our data suggest that in this mouse model of metabolic syndrome, expressing human PON1 inhibited the development of atherosclerosis, probably by reducing the amount of oxidized LDL in plasma and in the plaque, thereby preventing its proatherogenic effects. Adenovirus-mediated gene transfer of human PON1 may be a potential and useful tool to prevent/retard atherosclerosis in humans.
Mackness
Bharti
B
University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. bharti.mackness@cmmc.nhs.uk
Quarck
Rozenn
R
Verreth
Wim
W
Mackness
Mike
M
Holvoet
Paul
P
D000818:Animals; D043303:Aryldialkylphosphatase / Q000097:blood* / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D008076:Cholesterol, HDL / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D018014:Gene Transfer Techniques; D006801:Humans; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000097:blood; D024821:Metabolic Syndrome / Q000097:blood* / Q000150:complications*; D051379:Mice; D018345:Mice, Knockout
D008076:Cholesterol, HDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human