Chen Bo, Lu Yanrong, Chen Younan, Cheng Jingqiu
Key Laboratory of Transplant Engineering and ImmunologyMinistry of Health, Regenerative Medicine Research Center, West China Hospital, Sichuan University, No.1, Keyuan Road 4th, Wuhou District, Chengdu, Sichuan Province 610041, People's Republic of ChinaDepartment of Human AnatomySchool of Basic Medical Sciences, Luzhou Medicine College, Luzhou, People's Republic of China Key Laboratory of Transplant Engineering and ImmunologyMinistry of Health, Regenerative Medicine Research Center, West China Hospital, Sichuan University, No.1, Keyuan Road 4th, Wuhou District, Chengdu, Sichuan Province 610041, People's Republic of ChinaDepartment of Human AnatomySchool of Basic Medical Sciences, Luzhou Medicine College, Luzhou, People's Republic of China.
Key Laboratory of Transplant Engineering and ImmunologyMinistry of Health, Regenerative Medicine Research Center, West China Hospital, Sichuan University, No.1, Keyuan Road 4th, Wuhou District, Chengdu, Sichuan Province 610041, People's Republic of ChinaDepartment of Human AnatomySchool of Basic Medical Sciences, Luzhou Medicine College, Luzhou, People's Republic of China.
J Endocrinol. 2015 Jun;225(3):R83-99. doi: 10.1530/JOE-14-0662. Epub 2015 Apr 27.
Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.
内皮功能障碍是心血管疾病的重要危险因素，它是动脉粥样硬化发病机制的起始步骤。在大多数病理生理情况下，无法抵御氧化应激诱导的细胞损伤是导致内皮功能障碍的原因。众多抗氧化途径参与细胞氧化还原稳态，其中核因子E2相关因子2（Nrf2）/ Kelch样ECH相关蛋白1（Keap1）-抗氧化反应元件（ARE）信号通路可能最为突出。Nrf2是一种对氧化应激高度敏感的转录因子，它与细胞核中的ARE结合，促进多种抗氧化基因的转录。Nrf2位于细胞骨架中，与Keap1相邻。Keap1作为cullin 3 / ring-box 1介导的Nrf2泛素化和降解的衔接蛋白，在生理条件下降低Nrf2的活性。氧化应激导致Nrf2从Keap1解离，随后转移到细胞核中，导致其与ARE结合并转录下游靶基因。实验证据表明，Nrf2驱动的自由基解毒途径是重要的内源性稳态机制，与衰老、动脉粥样硬化、高血压、缺血和心血管疾病背景下的血管保护相关。本综述的目的是简要总结调节Nrf2 / Keap1-ARE信号通路的机制以及在理解Nrf2如何抵御氧化应激诱导的内皮损伤方面的最新进展。关于Nrf2调节内皮保护的确切机制的进一步研究对于确定Nrf2是否可作为心血管疾病治疗的靶点是必要的。
