Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation
Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation
复制标题
DOI：
10.1161/circulationaha.106.681700
复制
发表时间：
2007-04-17
期刊：
影响因子：
37.8
通讯作者：
Foerstermann, Ulrich
中科院分区：
文献类型：
--
作者：
Horke, Sven;Witte, Ines;Foerstermann, Ulrich
背景-在血管系统中，活性氧簇(ROS)水平升高会产生氧化应激，并易导致动脉粥样硬化的发生。因此，了解产生和清除血管ROS的系统是很重要的。在这里，我们分析了对氧磷酶-2(PON2)在不同的血管细胞中的ROS还原能力及其参与内质网应激途径的未折叠蛋白反应。方法和结果-定量实时聚合酶链式反应和Western blotting表明PON2在血管细胞中同样表达，并以两种不同的糖基化亚型出现。通过细胞内ROS的测定，我们发现PON2的过表达显著降低了ROS，而它的敲除显著增加了ROS的水平。利用显微镜和生化方法，我们发现PON_2主要分布在核膜和内质网中。此外，PON2在启动子和蛋白水平的表达都是通过内质网应激途径展开的蛋白反应来诱导的。这一途径可能同时促进了细胞的凋亡和存活机制。从功能上讲，PON2减少了伴随氧化应激的未折叠蛋白应答和未折叠蛋白应答衍生的caspase的激活。结论-我们认为PON2是一种内源性防御机制，可对抗血管氧化应激和未折叠蛋白应答诱导的细胞死亡，从而有助于预防动脉粥样硬化。
Background-In the vascular system, elevated levels of reactive oxygen species ( ROS) produce oxidative stress and predispose to the development of atherosclerosis. Therefore, it is important to understand the systems producing and those scavenging vascular ROS. Here, we analyzed the ROS-reducing capability of paraoxonase-2 ( PON2) in different vascular cells and its involvement in the endoplasmic reticulum stress pathway known as the unfolded protein response.Methods and Results-Quantitative real-time polymerase chain reaction and Western blotting revealed that PON2 is equally expressed in vascular cells and appears in 2 distinct glycosylated isoforms. By determining intracellular ROS, we show that overexpression of PON2 markedly reduced ROS, whereas its knockdown increased ROS levels significantly. Using microscopic and biochemical methods, we found PON2 mainly in the nuclear membrane and endoplasmic reticulum. Furthermore, PON2 expression was induced at both the promoter and protein levels by endoplasmic reticulum stress pathway unfolded protein response. This pathway may promote both apoptotic and survival mechanisms. Functionally, PON2 reduced unfolded protein response-accompanying oxidative stress and unfolded protein response-derived caspase activation.Conclusion-We suggest that PON2 represents an endogenous defense mechanism against vascular oxidative stress and unfolded protein response-induced cell death, thereby contributing to the prevention of atherosclerosis.