Mackness Bharti, Quarck Rozenn, Verreth Wim, Mackness Mike, Holvoet Paul
University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK.
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1545-50. doi: 10.1161/01.ATV.0000222924.62641.aa. Epub 2006 Apr 20.
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.
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.
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.
代谢综合征的特征为肥胖、血脂异常、糖尿病、高血压、氧化应激增加以及动脉粥样硬化加速。对氧磷酶1（PON1）是一种与高密度脂蛋白（HDL）相关的抗氧化酶，可防止低密度脂蛋白（LDL）氧化，在代谢综合征中其水平较低。
我们使用腺病毒介导的PON1基因转移（AdPON1）在瘦素和LDL受体联合缺乏的小鼠（一种代谢综合征模型）中过表达人PON1。将AdPON1小鼠的PON1活性、血脂、抗丙二醛（MDA）修饰LDL的自身抗体滴度以及动脉粥样硬化情况与接受对照重组腺病毒（AdRR5）的小鼠进行比较。AdPON1小鼠（N = 12）的PON1活性增加了4.4倍（P<0.001），而AdRR5小鼠（N = 11）的活性未改变。表达人PON1可显著减少总斑块体积、斑块巨噬细胞体积以及与斑块相关的氧化LDL体积。它增加了斑块中平滑肌细胞的百分比。表达人PON1降低了抗MDA修饰LDL的自身抗体滴度，这是小鼠中氧化LDL的替代指标。正如曲线下面积相似所证明的，它对血浆总胆固醇和甘油三酯以及HDL分布谱没有总体影响。
我们的数据表明，在这种代谢综合征小鼠模型中，表达人PON1可能通过减少血浆和斑块中氧化LDL的量来抑制动脉粥样硬化的发展，从而防止其促动脉粥样硬化作用。腺病毒介导的人PON1基因转移可能是预防/延缓人类动脉粥样硬化的一种潜在且有用的工具。
