Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases
Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases
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DOI：
10.1016/j.freeradbiomed.2015.05.027
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发表时间：
2015-11-01
影响因子：
7.4
通讯作者：
Pasini, Anna Fratta
中科院分区：
文献类型：
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作者：
Cominacini, Luciano;Mozzini, Chiara;Pasini, Anna Fratta
与人类疾病病理生理相关的各种细胞扰动，包括心血管和神经退行性疾病、糖尿病、肥胖和肝脏疾病，可以改变内质网（ER）功能并导致错误折叠蛋白的异常积累。这种情况构成了所谓的内质网压力，这是一种细胞内压力的形式，每当内质网的蛋白质折叠能力被淹没时就会发生。动脉粥样硬化性冠状动脉疾病导致组织缺氧，导致蛋白质错误折叠和内质网应激。此外，内质网应激在心脏肥厚中起重要作用，主要是在向心力衰竭（HF）过渡的过程中。内质网跨膜传感器检测未折叠蛋白的积累，并激活处理未折叠和错误折叠蛋白的转录和翻译途径，称为未折叠蛋白反应（UPR）。一旦HER不能控制内质网中未折叠和错误折叠蛋白的水平，内质网启动的凋亡信号传导就会被诱导。此外，有大量证据表明，氧化应激和随后的相关细胞损伤是缺血/再灌注（l/R）后心肌损伤和继发于压力过载的心肌肥大的初始原因。氧化应激是由一系列多种途径调节的复杂抗氧化防御系统来平衡的，包括HER，以确保对氧化剂的反应是充分的。核因子e2相关因子（Nrf2）是一种新兴的细胞抗氧化剂调节因子；Nrf2与称为胰腺内质网激酶的HER传感器密切相关。一系列研究表明，对内质网应激和Nrf2激活的干预分别减少了I/R损伤和压力过载动物向HF过渡时的心肌梗死面积和心肌肥厚。最后，最近的数据显示Nrf2/抗氧化反应元件通路的激活可能在缺血预处理中也很重要，缺血预处理是心脏在持续冠状动脉闭塞之前经历一次或多次非致死性心肌I/R发作的现象。(C) 2015爱思唯尔公司版权所有。
Various cellular cellular perturbations implicated in the pathophysiology of human diseases, including cardiovascular and neurodegenerative diseases, diabetes mellitus, obesity, and liver diseases, can alter endoplasmic reticulum (ER) function and lead to the abnormal accumulation of misfolded proteins. This situation configures the so-called ER stress, a form of intracellular stress that occurs whenever the protein folding capacity of the ER is overwhelmed. Reduction in blood How as a result of atherosclerotic coronary artery disease causes tissue hypoxia, a condition that induces protein misfolding and ER stress. In addition, ER stress has an important role in cardiac hypertrophy mainly in the transition to heart failure (HF). ER transmembrane sensors detect the accumulation of unfolded proteins and activate transcriptional and translational pathways that deal with unfolded and misfolded proteins, known as the unfolded protein response (UPR). Once the HER fails to control the level of unfolded and misfolded proteins in the ER, ER initiated apoptotic signaling is induced. Furthermore, there is considerable evidence that implicates the presence of oxidative stress and subsequent related cellular damage as an initial cause of injury to the myocardium after ischemia/reperfusion (l/R) and in cardiac hypertrophy secondary to pressure overload. Oxidative stress is counterbalanced by complex antioxidant defense systems regulated by a series of multiple pathways, including the HER, to ensure that the response to oxidants is adequate. Nuclear factor-E2-relared factor (Nrf2) is an emerging regulator of cellular resistance to oxidants; Nrf2 is strictly interrelated with the HER sensor called pancreatic endoplasmic reticulum kinase. A series of studies has shown that interventions against ER stress and Nrf2 activation reduce myocardial infarct size and cardiac hypertrophy in the transition to HF in animals exposed to I/R injury and pressure overload, respectively. Finally, recent data showed that Nrf2/antioxidant-response element pathway activation may be of importance also in ischemic preconditioning, a phenomenon in which the heart is subjected to one or more episodes of nonlethal myocardial I/R before the sustained coronary artery occlusion. (C) 2015 Elsevier Inc. All rights reserved.