Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis
Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis
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DOI：
10.1038/28406
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发表时间：
1998-07-16
期刊：
影响因子：
64.8
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
--
作者：
Shih, DM;Gu, LJ;Lusis, AJ
血清对氧磷酶 (PON1) 是一种与血浆中高密度脂蛋白 (HDL) 相关的酯酶；它参与对硫磷和毒死蜱等有机磷杀虫剂的解毒(1-3)。 PON1 还可以通过破坏氧化低密度脂蛋白 (LDL) 中的促炎氧化脂质来预防冠状动脉疾病(4-8)。为了研究 PON1 在体内的作用，我们通过基因靶向创建了 PON1 敲除小鼠。与野生型同窝小鼠相比，PON1缺陷小鼠对毒死蜱的活性形式毒死蜱oxon的毒性作用极其敏感，并且对毒死蜱本身更敏感。在共培养的动脉壁细胞模型中，从 PON1 缺陷小鼠中分离的 HDL 无法阻止 LDL 氧化，并且从 PON1 敲除小鼠中分离的 HDL 和 LDL 比来自野生型同窝小鼠的脂蛋白更容易被共培养细胞氧化。当喂食高脂肪、高胆固醇饮食时，PON1缺失小鼠比其野生型同窝小鼠更容易患动脉粥样硬化。
Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos(1-3). PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs)(4-8). To study the role of PON1 in vivo we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.