期刊
REDOX BIOLOGY
卷 21, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2018.11.021
关键词
Oxidative stress; NOXA1; Smooth muscle cells; KLF4; Macrophage-like cells; Atherosclerosis
资金
- National Institutes of Health, USA [HL111664, HL139842]
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 Noxal 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. Noxal 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. TNF alpha-induced ROS generation, proliferation and migration were significantly attenuated in Noxal -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 a-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据