Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia
Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia
复制标题
基于Nox4的平滑肌NADPH氧化酶在新生内膜增生中的作用
DOI：
10.1016/j.yjmcc.2015.11.013
复制
发表时间：
2015
影响因子：
5
通讯作者：
Cohen Richard A.
中科院分区：
文献类型：
--
作者：
Tong Xiaoyong;Kh;elwal Alok R.;Qin Zhexue;Wu Xiajuan;Chen Lili;Ago Tetsuro;Sadoshima Junichi;Cohen Richard A.
血管壁中活性氧（ROS）水平升高在新生内膜增生的发展中起关键作用。目的探讨Nox 4在血管新生内膜增生中的作用。方法和结果在小鼠中过量表达携带P437 H显性失活突变（Nox 4DN）的人Nox 4突变体（Nox 4DN），并由SM 22 α启动子驱动，使其在平滑肌细胞（SMC）中特异表达，在FVB/N遗传背景下产生。钢丝损伤诱导内皮剥脱后，与非转基因同窝对照组（NTg）相比，Nox 4DN显著降低了新生内膜形成。与NTg相比，从Nox 4DN分离的主动脉SMC中的ROS产生、血清诱导的增殖和迁移显著降低。血小板反应蛋白1（TSP 1）的mRNA和蛋白水平在Nox 4DN SMCs中均显著下调。通过siRNA下调TSP 1可降低SMC的细胞增殖和迁移。与Nox 4DN相似，siRNA下调Nox 4可显著降低TSP 1表达水平，抑制SMC增殖和迁移。结论Nox 4下调可通过抑制TSP 1抑制SMC增殖和迁移，从而抑制新生内膜增生。
Elevated levels of reactive oxygen species (ROS) in the vascular wall play a key role in the development of neointimal hyperplasia. Nox4-based NADPH oxidase is a major ROS generating enzyme in the vasculature, but its roles in neointimal hyperplasia remain unclear.ObjectiveOur purpose was to investigate the role of smooth muscle cell (SMC) Nox4 in neointimal hyperplasia.Approach and resultsMice overexpressing a human Nox4 mutant form, carrying a P437H dominant negative mutation (Nox4DN) and driven by SM22α promoter, to achieve specific expression in SMC, were generated in a FVB/N genetic background. After wire injury-induced endothelial denudation, Nox4DN had significantly decreased neointima formation compared with non-transgenic littermate controls (NTg). ROS production, serum-induced proliferation and migration, were significantly decreased in aortic SMCs isolated from Nox4DN compared with NTg. Both mRNA and protein levels of thrombospondin 1 (TSP1) were significantly downregulated in Nox4DN SMCs. Downregulation of TSP1 by siRNA decreased cell proliferation and migration in SMCs. Similar to Nox4DN, downregulation of Nox4 by siRNA significantly decreased TSP1 expression level, cell proliferation and migration in SMCs.ConclusionsDownregulation of smooth muscle Nox4 inhibits neointimal hyperplasia by suppressing TSP1, which in part can account for inhibition of SMC proliferation and migration.