p47phox is required for atherosclerotic lesion progression in ApoE-/- mice
p47phox is required for atherosclerotic lesion progression in ApoE-/- mice
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DOI：
10.1172/jci11927
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发表时间：
2001-11-01
影响因子：
15.9
通讯作者：
Runge, MS
中科院分区：
文献类型：
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作者：
Barry-Lane, PA;Patterson, C;Runge, MS
在平滑肌细胞（SMCs）中，受生长因子刺激，NADPH氧化酶上调，同时活性氧（ROS）的产生增加。我们研究了NADPH氧化酶产生ROS在ApoE（-/-）小鼠SMC对生长因子的反应和动脉粥样硬化病变形成中的作用。野生型、p47phox（-/-）和gp91phox（-/-）小鼠的SMCs在生长因子反应和ROS生成方面存在显著差异。与野生型细胞相比，p47phox(-/-) SMCs产生的超氧化物减少，对生长因子的增殖反应降低，而gp91phox(-/-) SMCs的反应与野生型SMCs没有区别。通过测量转基因小鼠(野生型、p47phox（-/-）、ApoE（-/-）和ApoE（-/-)/p47phox(-/-)）的动脉粥样硬化病变形成，验证了这些体外观察结果的相关性。无论给小鼠喂食标准食物还是高脂饮食，ApoE(-/-)/p47phox（-/-）小鼠的总损伤面积都小于ApoE（-/-）小鼠。总之，这些研究为超氧化物的产生，特别是NADPH氧化酶，在动脉粥样硬化病变形成中具有必要作用的假设提供了令人信服的支持，并为进一步研究ROS对血管病变形成的贡献提供了理论基础。
NADPH oxidase is upregulated in smooth muscle cells (SMCs) in response to growth factor stimulation, concomitant with increased reactive oxygen species (ROS) production. We investigated the role of ROS production by NADPH oxidase in SMC responses to growth factors and in atherosclerotic lesion formation in ApoE(-/-) mice. SMCs from wild-type, p47phox(-/-), and gp91phox(-/-) mice differed markedly with respect to growth factor responsiveness and ROS generation. p47phox(-/-) SMCs had diminished superoxide production and a decreased proliferative response to growth factors compared with wild-type cells, whereas the response of gp91phox(-/-) SMCs was indistinguishable from that of wild-type SMCs. The relevance of these in vitro observations was tested by measuring atherosclerotic lesion formation in genetically modified (wild-type, p47phox(-/-), ApoE(-/-), and ApoE(-/-)/p47phox(-/-)) mice. ApoE(-/-)/p47phox(-/-) mice had less total lesion area than ApoE(-/-) mice, regardless of whether mice were fed standard chow or a high-fat diet. Together, these studies provide convincing support for the hypothesis that superoxide generation in general, and NADPH oxidase in particular, have a requisite role in atherosclerotic lesion formation, and they provide a rationale for further studies to dissect the contributions of ROS to vascular lesion formation.