内皮细胞和平滑肌细胞氧化应激时Nrf2／ARE信号通路对抗氧化基因表达的调控:与动脉粥样硬化和先兆子痫的关系

Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress:implications for atherosclerosis and preeclampsia

动脉粥样硬化、糖尿病、慢性肾功能衰竭和先兆子痫等血管疾病时活性氧(reactive oxygen species,ROS)生成增加,容易导致内皮依赖性血管舒张功能的损害和血管损伤,而细胞可以诱导多种编码Ⅱ相解毒酶和抗氧化蛋白的基因表达,从而减轻ROS和亲电子物质介导的细胞损伤。一个被称为抗氧化反应元件(antioxidant response element,ARE)或亲电子反应元件(electrophile response element,EpRE)的顺式转录调控元件,可以介导诸如亚铁血红素加氧酶1、γ-谷氨酰半胱氨酸合成酶、硫氧还蛋白还原酶、谷胱甘肽-S转移酶和NAD(P)H:苯醌氧化还原酶等基因的转录。其他抗氧化酶,如超氧化物歧化酶、过氧化氢酶和非酶清除剂(如谷胱甘肽)等也参与ROS的清除。转录因子NF-E2相关因子2(nuclear factor-erythroid 2-related factor 2, Nrf2)是属于Cap‘n’Collar家族的转录因子,具有碱性亮氨酸拉链(basic region-leucine zipper,bZIP),它在ARE介导的抗氧化基因表达中起重要的作用。在正常情况下,Kelch样环氧氯丙烷相关蛋白-1(Kelch-like ECH-associated protein-1,Keapl)与Nrf2耦联,并与肌动蛋白细胞骨架结合被锚定于胞浆,但是在半胱氨酸残基发生氧化的情况下,Nrf2和Keapl解耦联,进入细胞核并与ARE结合,从而激活多种抗氧化基因和Ⅱ相解毒酶基因的转录。蛋白激酶C、丝裂原活化蛋白激酶和磷脂酰肌醇-3激酶参与Nrf2／ARE信号转导的调控。本文综述了有关Nrf2／ARE信号转导通路在血管稳态和动脉硬化、先兆子痫等疾病情况下内皮及平滑肌细胞对抗持续性氧化应激中起的作用。

Increased generation of reactive oxygen species （ROS） in vascular diseases such as atherosclerosis, diabetes, chronic renal failure and preeclampsia readily leads to impaired endothelium-dependent relaxation and vascular injury. To counteract ROS- and electrophile-mediated injury, cells can induce a number of genes encoding phase Ⅱ detoxifying enzymes and antioxidant proteins. A cisacting transcriptional regulatory element, designated as antioxidant response element （ARE） or electrophile response element （EpRE）, mediates the transcriptional activation of genes such as heme oxygenase-1, γ-glutamylcysteine synthethase, thioredoxin reductase, glutathione-S-transferase and NAD（P）H：quinone oxidoreductase. Other antioxidant enzymes such as superoxide dismutase and catalase and non-enzymatic scavengers such as glutathione are also involved in scavenging ROS. Nuclear factor-erythroid 2-related factor 2 （Nrf2）, a member of the Cap ＇n＇ Collar family of basic region-leucine zipper （bZIP） transcription factors, plays an important role in ARE-mediated antioxidant gene expression. Kelch-like ECH-associated protein-1 （Keap 1） normally sequesters Nrf2 in the cytoplasm in, association with the actin cytoskeleton, but upon oxidation of cysteine residues Nrf2 dissociates from Keapl, translocates to the nucleus and binds to ARE sequences leading to transcriptional activation of antioxidant and phase II detoxifying genes. Protein kinase C （PKC）, mitogen-activated protein kinases （MAPKs） and phosphotidylinositol 3-kinase （PI3K） have been implicated in the regulation of Nrf2/ARE signaling. We here review the evidence that the Nrf2/ARE signaling pathway plays an important role in vascular homeostasis and the defense of endothelial and smooth muscle cells against sustained oxidative stress associated with diseases such as atherosclerosis and preeclampsia.