Vendrov Aleksandr E, Hakim Zeenat S, Madamanchi Nageswara R, Rojas Mauricio, Madamanchi Chaitanya, Runge Marschall S
Department of Medicine, University of North Carolina at Chapel Hill, 3033 Old Clinic Building, Chapel Hill, NC 27599-7005, USA.
Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2714-21. doi: 10.1161/ATVBAHA.107.152629. Epub 2007 Sep 6.
We previously showed that NAD(P)H oxidase deficiency significantly reduces atherosclerosis in apoE(-/-) mice. The present study was designed to determine the relative contribution of monocyte/macrophage versus vascular wall cell NAD(P)H oxidase to atherogenesis in this model.
Cell-specific NAD(P)H oxidase inhibition was achieved via allogenic, sex-mismatched bone marrow transplantation. Aortic atherosclerosis and superoxide production in apoE(-/-) mice (Control) with functional NAD(P)H oxidase in both monocytes/macrophages and vascular wall cells was compared with that in apoE(-/-) mice with nonfunctional monocyte/macrophage NAD(P)H oxidase (BMO) or nonfunctional vessel wall NAD(P)H oxidase (VWO). A significant decrease in superoxide production and atherosclerotic lesions was observed in BMO and VWO mice compared with control mice. Interestingly, BMO mice had significantly lower plasma oxidized LDL levels compared with control and VWO mice, whereas aortic sections of VWO mice showed decreased expression of cellular adhesion molecules compared with control and BMO mice. NAD(P)H oxidase deficiency also attenuated neointimal hyperplasia and mitogenic protein activation in apoE(-/-) mice after arterial injury.
We conclude that (1) both monocyte/macrophages and vessel wall cells play critical roles in atherogenesis; (2) decrease in atherosclerosis results from attenuated superoxide generation in monocyte/macrophages or vessel wall cells; and (3) superoxide generation may impact atherosclerosis, in part, by activating smooth muscle cell mitogenic signaling pathways.
我们之前的研究表明，NAD(P)H氧化酶缺乏可显著减轻载脂蛋白E基因敲除（apoE(-/-)）小鼠的动脉粥样硬化。本研究旨在确定在该模型中，单核细胞/巨噬细胞与血管壁细胞NAD(P)H氧化酶对动脉粥样硬化发生的相对作用。
通过同种异体、性别不匹配的骨髓移植实现细胞特异性NAD(P)H氧化酶抑制。将单核细胞/巨噬细胞和血管壁细胞中具有功能性NAD(P)H氧化酶的apoE(-/-)小鼠（对照组）的主动脉粥样硬化和超氧化物生成情况，与单核细胞/巨噬细胞NAD(P)H氧化酶无功能的apoE(-/-)小鼠（BMO组）或血管壁NAD(P)H氧化酶无功能的apoE(-/-)小鼠（VWO组）进行比较。与对照组小鼠相比，BMO组和VWO组小鼠的超氧化物生成和动脉粥样硬化病变显著减少。有趣的是，与对照组和VWO组小鼠相比，BMO组小鼠的血浆氧化型低密度脂蛋白水平显著降低，而与对照组和BMO组小鼠相比，VWO组小鼠的主动脉切片显示细胞黏附分子表达减少。NAD(P)H氧化酶缺乏还可减轻apoE(-/-)小鼠动脉损伤后的内膜增生和有丝分裂原蛋白激活。
我们得出以下结论：（1）单核细胞/巨噬细胞和血管壁细胞在动脉粥样硬化发生中均起关键作用；（2）动脉粥样硬化的减轻是由于单核细胞/巨噬细胞或血管壁细胞中超氧化物生成减少；（3）超氧化物生成可能部分通过激活平滑肌细胞有丝分裂信号通路影响动脉粥样硬化。
