Induced peroxidase and cytoprotective enzyme expressions support adaptation of HUVECs to sustain subsequent H2O2 exposure.
Induced peroxidase and cytoprotective enzyme expressions support adaptation of HUVECs to sustain subsequent H2O2 exposure.
复制标题
诱导的过氧化物酶和细胞保护酶表达支持 HUVEC 的适应以维持随后的 H2O2 暴露。
DOI：
10.1016/j.mvr.2015.09.003
复制
发表时间：
2016-01
影响因子：
3.1
通讯作者：
Kavdia M
中科院分区：
文献类型：
--
作者：
Patel H;Chen J;Kavdia M
H2O2介导血管系统中的自分泌和旁分泌信号，并可传播内皮功能障碍。然而，目前尚不清楚内皮细胞如何承受H2O2暴露并促进H2O2诱导的血管重塑。为了了解内皮细胞维持过量H2O2暴露的先天能力，我们研究了H2O2处理后原代HUVECs中氧化还原系统的基因型和功能调节。原代HUVECs暴露于两种类型的H2O2治疗的短暂和一致的H2O2暴露。在H2O2处理24、48和72小时后，我们测量了O2 −的产生、线粒体膜极化（MMP）以及前氧化酶、过氧化物酶和细胞保护中间体的基因表达。我们的研究结果表明，24小时H2O2暴露显著增加了O2−水平，超极化MMP，并下调了HUVECs中CAT，GPX1，TXNRD1，NFE 2L2，ASK 1和ATF 2基因的表达。在72小时时，两种处理条件下的HUVEC均显示出适应性，以降低O2−水平并使MMP正常化。在48和72小时的持续和短暂治疗中观察到GPX 1、TXNRD 1和HMOX 1基因表达上调以及NFE 2L2和PRDX 1基因表达恢复至对照水平。内皮细胞对过量H2O2的反应涉及O2−水平、线粒体膜极化以及抗氧化剂和促氧化剂基因调控之间的复杂相互作用。作为这种反应的一部分，HUVEC诱导细胞保护机制，包括过氧化物酶和抗氧化酶的表达沿着促凋亡基因的下调。这种适应有助于HUVEC承受随后的H2O2暴露
H2O2 mediates autocrine and paracrine signaling in the vasculature and can propagate endothelial dysfunction. However, it is not clear how endothelial cells withstand H2O2 exposure and promote H2O2-induced vascular remodeling. To understand the innate ability of endothelial cells for sustaining excess H2O2 exposure, we investigated the genotypic and functional regulation of redox systems in primary HUVECs following an H2O2 treatment. Primary HUVECs were exposed to two types of H2O2 treatments of both transient and consistent H2O2 exposure. Following H2O2 treatments for 24, 48 and 72 hr, we measured O 2− production, mitochondrial membrane polarization (MMP), and gene expressions of pro-oxidative enzymes, peroxidase enzymes, and cytoprotective intermediates. Our results showed that the 24 hr H2O2 exposure significantly increased O2− levels, hyperpolarized MMP, and downregulated CAT, GPX1, TXNRD1, NFE2L2, ASK1, and ATF2 gene expression in HUVECs. At 72 hr, HUVECs in both treatment conditions were shown to adapt to reduce O2− levels and normalize MMP. An upregulation of GPX1, TXNRD1, and HMOX1 gene expression and a recovery of NFE2L2 and PRDX1 gene expression to control levels were observed in both consistent and transient treatments at 48 and 72 hr. The response of endothelial cells to excess levels of H2O2 involves a complex interaction amongst O2− levels, mitochondrial membrane polarization and anti- and pro-oxidant gene regulation. As a part of this response, HUVECs induce cytoprotective mechanisms including the expression of peroxidase and antioxidant enzymes along with the downregulation of pro-apoptotic genes. This adaptation assists HUVECs to withstand subsequent exposures to H2O2