Increased reactive oxygen species (ROS) production and inflammation are key factors in the pathogenesis of atherosclerosis. We previously reported that NOX activator 1 (NOXA1) is the critical functional homolog of p67phox for NADPH oxidase activation in mouse vascular smooth muscle cells (VSMC). Here we investigated the effects of systemic and SMC-specific deletion of Noxa1 on VSMC phenotype during atherogenesis in mice.

Neointimal hyperplasia following endovascular injury was lower in Noxa1-deficient mice versus the wild-type following endovascular injury. Noxa1 deletion in Apoe^-/- or Ldlr^-/- mice fed a Western diet showed 50% reduction in vascular ROS and 30% reduction in aortic atherosclerotic lesion area and aortic sinus lesion volume (P < 0.01). SMC-specific deletion of Noxa1 in Apoe^-/- mice (Noxa1^SMC-/-/Apoe^-/-) similarly decreased vascular ROS levels and atherosclerotic lesion size. TNFα-induced ROS generation, proliferation and migration were significantly attenuated in Noxa1-deficient versus wild-type VSMC. Immunofluorescence analysis of atherosclerotic lesions showed a significant decrease in cells positive for CD68 and myosin11 (22% versus 9%) and Mac3 and α-actin (17% versus 5%) in the Noxa1^SMC-/-/Apoe^-/- versus Apoe^-/- mice. The expression of transcription factor KLF4, a modulator of VSMC phenotype, and its downstream targets – VCAM1, CCL2, and MMP2 – were significantly reduced in the lesions of Noxa1^SMC-/-/Apoe^-/- versus Apoe^-/- mice as well as in oxidized phospholipids treated Noxa1^SMC-/- versus wild-type VSMC.

Our data support an important role for NOXA1-dependent NADPH oxidase activity in VSMC plasticity during restenosis and atherosclerosis, augmenting VSMC proliferation and migration and KLF4-mediated transition to macrophage-like cells, plaque inflammation, and expansion.

活性氧（ROS）产生和炎症的增加是动脉粥样硬化发病机理中的关键因素。我们以前报道过，NOX激活剂1（NOXA1）是p67phox在小鼠血管平滑肌细胞（VSMC）中对NADPH氧化酶激活的关键功能同源物。在这里，我们研究了在小鼠动脉粥样硬化过程中Noxa1全身性和SMC特异性缺失对VSMC表型的影响。

Noxa1缺陷小鼠的血管内损伤后新内膜增生低于血管内损伤后的野生型。用西方饮食喂养的Apoe ^-/-或Ldlr ^-/-小鼠中Noxa1缺失显示血管ROS减少50％，主动脉粥样硬化病变面积和主动脉窦病变体积减少30％（P  <0.01）。的SMC-特异性缺失Noxa1在APOE ^{/ - -}小鼠（Noxa1 ^{SMC - / -} / APOE ^{- / -}）同样降低了血管ROS水平和动脉粥样硬化病变的大小。TNFα诱导的ROS的产生，增殖和迁移在Noxa1缺陷型和野生型VSMC中显着减弱。动脉粥样硬化病变的免疫荧光分析显示，Noxa1 ^SMC-/- / Apoe ^-/-与Apoe相比，CD68和myosin11阳性细胞的细胞显着减少（22％对9％）以及Mac3和α-actin（17％对5％）。^-/-老鼠。在Noxa1 ^SMC-/- / Apoe ^-/-的病变中，VSMC表型的调节因子转录因子KLF4的表达及其下游靶标VCAM1，CCL2和MMP2显着降低。与Apoe ^-/-小鼠相比，以及在氧化磷脂中处理的Noxa1 ^SMC-/-与野生型VSMC相比。

我们的数据支持NOXA1依赖性NADPH氧化酶活性在再狭窄和动脉粥样硬化过程中在VSMC可塑性中的重要作用，增加VSMC的增殖和迁移以及KLF4介导的向巨噬细胞样细胞的过渡，斑块炎症和扩张。