Lee Moo Yeol, San Martin Alejandra, Mehta Puja K, Dikalova Anna E, Garrido Abel Martin, Datla S Raju, Lyons Erin, Krause Karl-Heinz, Banfi Botond, Lambeth J David, Lassègue Bernard, Griendling Kathy K
Emory University, Department of Medicine, Division of Cardiology, Atlanta, GA 30322, USA.
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):480-7. doi: 10.1161/ATVBAHA.108.181925. Epub 2009 Jan 15.
Vascular NADPH oxidases (Noxes) have been implicated in cardiovascular diseases; however, the importance of individual Nox homologues remains unclear. Here, the role of the vascular smooth muscle cell (VSMC) Nox1 in neointima formation was studied using genetically modified animal models.
Wire injury-induced neointima formation in the femoral artery, along with proliferation and apoptosis, was reduced in Nox1(y/-) mice, but there was little difference in Tg(SMCnox1) mice compared with wild-type (WT) mice. Proliferation and migration were reduced in cultured Nox1(y/-) VSMCs and increased in Tg(SMCnox1) cells. Tg(SMCnox1) cells exhibited increased fibronectin secretion, but neither collagen I production nor cell adhesion was affected by alteration of Nox1. Using antibody microarray and Western blotting analysis, increased cofilin phosphorylation and mDia1 expression and decreased PAK1 expression were detected in Nox1(y/-) cells. Overexpression of S3A, a constitutively active cofilin mutant, partially recovered reduced migration of Nox1(y/-) cells, suggesting that reduction in cofilin activity contributes to impaired migration of Nox1(y/-) VSMCs.
These results indicate that Nox1 plays a critical role in neointima formation by mediating VSMC migration, proliferation, and extracellular matrix production, and that cofilin is a major effector of Nox1-mediated migration. Inhibition of Nox1 may be an efficient strategy to suppress neointimal formation.
血管NADPH氧化酶（Noxes）与心血管疾病有关；然而，单个Nox同源物的重要性仍不清楚。在此，使用基因改造动物模型研究了血管平滑肌细胞（VSMC）Nox1在新生内膜形成中的作用。
Nox1(y/-)小鼠股动脉中钢丝损伤诱导的新生内膜形成以及增殖和凋亡减少，但与野生型（WT）小鼠相比，Tg(SMCnox1)小鼠几乎没有差异。培养的Nox1(y/-)VSMC中增殖和迁移减少，而Tg(SMCnox1)细胞中增殖和迁移增加。Tg(SMCnox1)细胞表现出纤连蛋白分泌增加，但Nox1改变对I型胶原产生和细胞黏附均无影响。使用抗体微阵列和蛋白质印迹分析，在Nox1(y/-)细胞中检测到丝切蛋白磷酸化增加、mDia1表达增加和PAK1表达减少。组成型活性丝切蛋白突变体S3A的过表达部分恢复了Nox1(y/-)细胞减少的迁移，表明丝切蛋白活性降低导致Nox1(y/-)VSMC迁移受损。
这些结果表明，Nox1通过介导VSMC迁移、增殖和细胞外基质产生在新生内膜形成中起关键作用，并且丝切蛋白是Nox1介导迁移的主要效应器。抑制Nox1可能是抑制新生内膜形成的有效策略。
