Expression of human myeloperoxidase by macrophages promotes atherosclerosis in mice
Expression of human myeloperoxidase by macrophages promotes atherosclerosis in mice
复制标题
DOI：
10.1161/circulationaha.104.516278
复制
发表时间：
2005-05-31
期刊：
影响因子：
37.8
通讯作者：
LeBoeuf, RC
中科院分区：
文献类型：
--
作者：
McMillen, TS;Heinecke, JW;LeBoeuf, RC
背景 - 髓过氧化物酶 (MPO) 与人体动脉壁中的巨噬细胞共存，其特征性氧化产物已在动脉粥样硬化病变中检测到。因此，酶产生的氧化剂可能会促进动脉粥样硬化。然而，小鼠动脉粥样硬化组织中的巨噬细胞不表达 MPO。因此，小鼠不适合用于测试 MPO 在血管疾病中的作用。为了克服这个问题，我们生成并研究了含有人类 MPO 基因的转基因 (Tg) 小鼠。方法和结果 - 我们使用 Visna 病毒启动子生成了人类 MPO-Tg 小鼠。为了将 MPO 表达限制在巨噬细胞中，我们对 LDL 受体缺陷小鼠进行致命辐射，并用来自野生型小鼠或 MPO-Tg 小鼠的细胞重新填充其骨髓。尽管维持高脂肪、高胆固醇饮食后胆固醇水平相似，但 MPO-Tg 动物的主动脉粥样硬化区域比移植野生型骨髓的小鼠大 2 倍 (P = 0.00003)。 结论 - 我们的观察表明，巨噬细胞中人 MPO 的表达会促进高胆固醇血症小鼠的动脉粥样硬化，从而提高了该酶可能成为潜在治疗药物的可能性预防人类心血管疾病的目标。
Background - Myeloperoxidase (MPO) colocalizes with macrophages in the human artery wall, and its characteristic oxidation products have been detected in atherosclerotic lesions. Thus, oxidants produced by the enzyme might promote atherosclerosis. However, macrophages in mouse atherosclerotic tissue do not express MPO. Therefore, mice are an inappropriate model for testing the role of MPO in vascular disease. To overcome this problem, we generated and studied transgenic (Tg) mice that contained the human MPO gene.Methods and Results - We produced human MPO-Tg mice with use of a Visna virus promoter. To confine MPO expression to macrophages, we lethally irradiated LDL receptor - deficient mice and repopulated their bone marrow with cells from wild-type mice or MPO-Tg mice. Despite having similarly high levels of cholesterol after maintenance on a high-fat, high-cholesterol diet, the MPO-Tg animals developed a 2-fold greater atherosclerotic area in the aorta than did mice transplanted with wild-type bone marrow (P = 0.00003).Conclusions - Our observations indicate that expression of human MPO in macrophages promotes atherosclerosis in hypercholesterolemic mice, raising the possibility that the enzyme might be a potential therapeutic target for preventing cardiovascular disease in humans.