VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal-regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms.
VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal-regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms.
复制标题
VPO1 通过激活腹主动脉瘤中的细胞外信号调节激酶 1/2 (ERK 1/2) 来调节血管平滑肌细胞表型转换
DOI：
10.1161/jaha.118.010069
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发表时间：
2018-09-04
影响因子：
5.4
通讯作者：
Zhang G
中科院分区：
文献类型：
--
作者：
Peng H;Zhang K;Liu Z;Xu Q;You B;Li C;Cao J;Zhou H;Li X;Chen J;Cheng G;Shi R;Zhang G
过氧化氢（H2O2）是腹主动脉瘤（AAA）形成过程中的关键分子信号。血管过氧化物酶1 （VPO1）能催化H2O2生成次氯酸（HOCl），显著增强氧化应激。血管平滑肌细胞（VSMCs）从收缩表型到合成表型的转变是由活性氧驱动的，被认为是AAA形成的早期和重要事件。本研究旨在确定VPO1是否通过调节VSMC表型开关在AAA的发展中起关键作用。与健康对照组织相比，VPO1在人和弹性蛋白酶诱导的小鼠动脉瘤组织中表达上调。此外，核转录因子KLF4在动脉瘤组织中上调，同时分化平滑肌细胞标记下调，合成表型标记增加，表明这些病变组织中存在VSMC表型开关。在培养的大鼠腹主动脉VSMC中，H2O2处理显著提高VPO1表达和HOCl水平，并显著提高VSMC表型开关。为了支持这些发现，VPO1的耗尽显著减弱H2O2和HOCl处理的效果。此外，HOCl处理促进VSMC表型开关和ERK1/2磷酸化。U0126 （ERK1/2的特异性抑制剂）预处理可显著减弱HOCl诱导的VSMC表型开关。我们的研究结果表明，VPO1通过H2O2/VPO1/HOCl/ERK1/2信号通路调节VSMC表型开关，并在AAA的发展中发挥关键作用，我们的研究结果也暗示VPO1是一个新的信号节点，介导VSMC表型开关，并在AAA的发展中发挥关键作用。唯一标识符：ChiCTR1800016922。
Hydrogen peroxide (H2O2) is a critical molecular signal in the development of abdominal aortic aneurysm (AAA) formation. Vascular peroxidase 1 (VPO1) catalyzes the production of hypochlorous acid (HOCl) from H2O2 and significantly enhances oxidative stress. The switch from a contractile phenotype to a synthetic one in vascular smooth muscle cells (VSMCs) is driven by reactive oxygen species and is recognized as an early and important event in AAA formation. This study aims to determine if VPO1 plays a critical role in the development of AAA by regulating VSMC phenotypic switch. VPO1 is upregulated in human and elastase‐induced mouse aneurysmal tissues compared with healthy control tissues. Additionally, KLF4, a nuclear transcriptional factor, is upregulated in aneurysmatic tissues along with a concomitant downregulation of differentiated smooth muscle cell markers and an increase of synthetic phenotypic markers, indicating VSMC phenotypic switch in these diseased tissues. In cultured VSMCs from rat abdominal aorta, H2O2 treatment significantly increases VPO1 expression and HOCl levels as well as VSMC phenotypic switch. In support of these findings, depletion of VPO1 significantly attenuates the effects of H2O2 and HOCl treatment. Furthermore, HOCl treatment promotes VSMC phenotypic switch and ERK1/2 phosphorylation. Pretreatment with U0126 (a specific inhibitor of ERK1/2) significantly attenuates HOCl‐induced VSMC phenotypic switch. Our results demonstrate that VPO1 modulates VSMC phenotypic switch through the H2O2/VPO1/HOCl/ERK1/2 signaling pathway and plays a key role in the development of AAA. Our findings also implicate VPO1 as a novel signaling node that mediates VSMC phenotypic switch and plays a key role in the development of AAA. URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1800016922.