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/jci200111927
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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
NADPH氧化酶在平滑肌细胞（SMC）中响应于生长因子刺激而上调，伴随着活性氧（ROS）产生的增加。我们研究了NADPH氧化酶产生的ROS在SMC对生长因子的反应和ApoE（-/-）小鼠动脉粥样硬化病变形成中的作用。野生型、p47 phox（-/-）和gp 91 phox（-/-）小鼠的SMC在生长因子反应性和活性氧产生方面存在显着差异。与野生型细胞相比，p47 phox（-/-）SMCs的超氧化物产生减少，对生长因子的增殖反应降低，而gp 91 phox（-/-）SMCs的反应与野生型SMCs的反应没有区别。通过测量转基因（野生型、p47 phox（-/-）、ApoE（-/-）和ApoE（-/-）/p47 phox（-/-））小鼠中动脉粥样硬化病变形成来检验这些体外观察结果的相关性。ApoE（-/-）/p47 phox（-/-）小鼠的总病变面积小于ApoE（-/-）小鼠，无论小鼠是喂食标准食物还是高脂饮食。总之，这些研究提供了令人信服的支持的假设，即超氧化物生成一般，特别是NADPH氧化酶，有必要的作用，动脉粥样硬化病变的形成，他们提供了一个理论基础，进一步研究解剖的ROS血管病变形成的贡献。
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.