Nox2 regulates endothelial cell cycle arrest and apoptosis via p21cip1 and p53.
Nox2 regulates endothelial cell cycle arrest and apoptosis via p21cip1 and p53.
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DOI：
10.1016/j.freeradbiomed.2007.06.001
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发表时间：
2007-09-15
影响因子：
7.4
通讯作者：
Brooks, Gavin
中科院分区：
文献类型：
--
作者：
Li, Jian-Mei;Fan, Lampson M.;George, Vinoj T.;Brooks, Gavin
内皮细胞（EC）组成性表达NADPH氧化酶催化亚基的两种主要亚型（Nox 2和Nox 4），NADPH氧化酶是内皮活性氧的主要来源。然而，这些Noxes在内皮功能中的个体作用仍不清楚。我们研究了Nox 2在营养缺乏诱导的细胞周期阻滞和凋亡中的作用。在增殖的人真皮微血管内皮细胞中，Nox 2 mRNA的表达相对于Nox 4低（Nox 2：Nox 4 ~1：13），但在饥饿后24 h表达上调，饥饿36 h时增加到8 ± 3.5倍。伴随着Nox 2的上调，O2·−的产生增加了2.28±0.18倍，p21 cip 1和p53的显著诱导，细胞周期停滞和凋亡的开始（所有p<0.05）。所有这些变化都受到抑制显着的Nox 2表达的体外删除和从Nox 2基因敲除小鼠的冠状动脉微血管EC分离。在Nox 2敲除细胞中，尽管饥饿36 h后Nox 4 mRNA表达增加了3.8±0.5倍（p<0.01），但O2·−产生和p21 cip 1或p53表达均未显著增加，仅0.46%的细胞发生凋亡。总之，Nox 2源性O2·−通过调节p21 cip 1和p53的表达，参与内皮细胞周期调节和凋亡。
Endothelial cells (EC) express constitutively two major isoforms (Nox2 and Nox4) of the catalytic subunit of NADPH oxidase, which is a major source of endothelial reactive oxygen species. However, the individual roles of these Noxes in endothelial function remain unclear. We have investigated the role of Nox2 in nutrient deprivation-induced cell cycle arrest and apoptosis. In proliferating human dermal microvascular EC, Nox2 mRNA expression was low relative to Nox4 (Nox2:Nox4 ~1:13), but was upregulated 24 h after starvation and increased to 8 ± 3.5-fold at 36 h of starvation. Accompanying the upregulation of Nox2, there was a 2.28±0.18-fold increase in O2•− production, a dramatic induction of p21cip1 and p53, cell cycle arrest, and the onset of apoptosis (all p<0.05). All these changes were inhibited significantly by in vitro deletion of Nox2 expression and in coronary microvascular EC isolated from Nox2 knockout mice. In Nox2 knockout cells, although there was a 3.8±0.5-fold increase in Nox4 mRNA expression after 36 h of starvation (p<0.01), neither O2•− production nor the p21cip1 or p53 expression was increased significantly and only 0.46% of cells were apoptotic. In conclusion, Nox2-derived O2•−, through the modulation of p21cip1 and p53 expression, participates in endothelial cell cycle regulation and apoptosis.
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