内质网应激与心血管疾病

内质网作为维持细胞生命活动的重要细胞器,在遭受损伤时可引起以未折叠蛋白反应为特点的内质网应激（ERS）反应。ERS一方面可以诱导促生存信号通路的激活以减轻细胞损伤;另一方面也可以通过激活损伤相关信号通路引发细胞凋亡。ERS参与了心衰、心肌缺血一再灌注损伤以及心肌病的发生和发展,其可能成为研究心血管疾病发病机制和防治手段的新靶点。     

内质网应激与糖尿病相关性研究进展

内质网应激(ERS)是一种特殊类型的细胞内应激,是由内质网内错误折叠与未折叠蛋白聚集以及Ca+代谢紊乱所引起.研究表明,适度ERS通过激活未折叠蛋白反应起适应性的细胞保护作用,而过高和持久的ERS则通过诱导转录因子CHOP表达、激活caspase-12和c-Jun氨基末端激酶(JNK)等导致细胞凋亡.近年的研究显示,ERS通过促使胰岛β细胞凋亡及胰岛素抵抗参与糖尿病发病,而阻断ERS诱导的凋亡通路和胰岛素抵抗则可能为糖尿病治疗提供新的手段.     

内质网应激、凋亡及心血管疾病△

内质网是真核细胞中一个参与蛋白质合成、加工与修饰的重要细胞器,它对维持细胞内环境的稳定具有重要意义。内质网应激是一种因各种生理或病理因素诱发内质网紊乱而导致非折叠蛋白堆积所造成的一种状态。内质网应激能激发非折叠蛋白反应以恢复细胞内稳态或者细胞凋亡。这篇综述重点阐述内质网应激参与心血管疾病发生、发展的分子机制及治疗。     

内质网应激与缺血性脑损伤

内质网应激是内质网内未折叠或错误折叠蛋白积聚所致。作为对内质网应激的响应,细胞形成了一条称为未折叠蛋白反应(UPR)的自我保护信号转导通路。然而,如果脑缺血诱导的内质网应激严重且持续时间长,UPR最终会启动细胞凋亡通路,导致神经元死亡。文章对脑缺血再灌注诱导内质网应激和UPR的研究进展做了综述。     

内质网应激与肝细胞凋亡

内质网(endoplasmic reticulum,ER)是一种重要的真核细胞器,由于各种原因引起的内质网中出现错误折叠与未折叠蛋白在腔内聚集以及Ca~(2 )平衡紊乱的状态,称为内质网应激(ER stress,ERS).细胞凋亡(apoptosis),又称为程序性细胞死亡(programmed cell death,PCD),是受细胞外微环境和细胞内基因调控的一种细胞主动性死亡方式,他是机体用来去除衰老、有害、无用及异型细胞的一种重要机制,是确保机体正常发育、维持机体正常生理过程所必须的.肝细胞凋亡是造成肝脏损伤和肝脏疾病最基本的中心环节.既往研究认为肝细胞凋亡主要通过两条信号通路介导,即死亡受体通路和线粒体依赖性的细胞凋亡通路.但近来发现ERS亦介导肝细胞发生凋亡,本文主要讨论ERS途径所致肝细胞凋亡的机制.     

内质网应激与心血管疾病

内质网是细胞内蛋白质合成、折叠以及钙离子储存部位。内质网稳态失衡会诱导内质网应激,在早期应激力图恢复内质网稳态从而发挥保护作用,但持久应激会导致细胞凋亡。多项研究显示内质网应激诱导细胞凋亡与心血管疾病密切相关,对内质网应激进行干预可能成为心血管疾病治疗的新靶点。     

未折叠蛋白反应-内质网自噬在心血管疾病中的研究进展

未折叠蛋白反应（unfolded protein response,UPR）是在病理因素刺激下,由于错误蛋白聚集在内质网诱导细胞核减少蛋白合成以缓解内质网压力的保护措施。内质网自噬是溶酶体特异性选择降解受损内质网的代谢过程。UPR和内质网自噬的表达关系可以是协同,亦可是拮抗,更重要的是,将UPR-内质网自噬调节至正常水平范围内,这将更有利于心肌细胞生存。本文将概述未折叠蛋白反应-内质网自噬在心血管疾病（cardiovascular disease,CVD）中的研究进展。     

内质网应激与溃疡性结肠炎

内质网应激(ERS)是各种原因引起的错误折叠或未折叠蛋白质在内质网腔中聚集导致的稳态失衡,介导ERS的通路有3条,通路起始蛋白分别为肌醇需求激酶1(IRE1)、蛋白激酶R样内质网激酶(PERK)和活化转录因子6(ATF6)。大量研究发现ERS在溃疡性结肠炎(UC)的发病中起着重要的作用。该文就ERS与UC关系的相关研究进展作一综述。     

内质网应激与病毒性肝炎

在病理条件下,未折叠蛋白或者错误折叠蛋白在内质网内的大量聚集,影响内质网的稳态和正常功能,引发未折叠蛋白反应,称为内质网应激。研究表明,内质网应激对细胞凋亡、炎症反应以及病毒复制都有影响,因此参与各种肝病的发生和发展。本文重点对内质网应激和病毒性肝炎的关系进行阐述。     

内质网应激在非酒精性脂肪性肝病发病机制中的作用

非酒精性脂肪性肝病(NAFLD)的发病率在全球范围内迅速增加,但其发病的确切机制并不十分清楚。一方面探讨内质网应激(ERS)可以通过未折叠氮蛋白反应(URP)促进NAFLD的形成及进展为非酒精性脂肪性肝炎(NASH),另一方面探讨NAFLD的脂质环境,尤其是脂肪酸,又可诱发ERS的发生。从而指出ERS相关信号转导在NAFLD发病机制中的作用,为NAFLD的治疗提供新的思路。     

Endoplasmic reticulum stress and cardiovascular diseases

The endoplasmic reticulum (ER) serves several important functions, mainly post-translational modification, folding and assembly of newly synthesized secretary proteins, synthesizing lipids and cellular calcium storage. Various factors can disrupt ER homeostasis and disturb its functions, which leads to the accumulation of unfolded and misfolded proteins and to potential cellular dysfunction and pathological consequences, collectively termed ER stress. Recent progress suggests that ER stress plays a key role in the immune response, diabetes, tumor growth, and some neurodegenerative diseases. In particular, ER stress is involved in several processes of cardiovascular diseases, such as ischemia/reperfusion injury, cardiomyopathy, cardiac hypertrophy, heart failure, and atherosclerosis. Further research on the relation of ER stress to cardiovascular diseases will greatly enhance the understanding of these pathological processes and provide novel avenues to potential therapies.     

BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress

B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) is a BCL-2 family protein with high homology to the multidomain proapoptotic proteins BAX and BAK, yet Bok^−/− and even Bax^−/−Bok^−/− and Bak^−/−Bok^−/− mice were reported to have no overt phenotype or apoptotic defects in response to a host of classical stress stimuli. These surprising findings were interpreted to reflect functional compensation among the BAX, BAK, and BOK proteins. However, BOK cannot compensate for the severe apoptotic defects of Bax^−/−Bak^−/− mice despite its widespread expression. Here, we independently developed Bok^−/− mice and found that Bok^−/− cells are selectively defective in their response to endoplasmic reticulum (ER) stress stimuli, consistent with the predominant subcellular localization of BOK at the ER. Whereas Bok^−/− mouse embryonic fibroblasts exposed to thapsigargin, A23187, brefeldin A, DTT, geldanamycin, or bortezomib manifested reduced activation of the mitochondrial apoptotic pathway, the death response to other stimuli such as etoposide, staurosporine, or UV remained fully intact. Multiple organs in Bok^−/− mice exhibited resistance to thapsigargin-induced apoptosis in vivo. Although the ER stress agents activated the unfolded protein response, both ATF4 and CHOP activation were diminished in Bok^−/− cells and mice. Importantly, BAX and BAK were unable to compensate for the defective apoptotic response to ER stress observed in SV40-transformed and primary Bok^−/− cells, and in vivo. These findings support a selective and distinguishing role for BOK in regulating the apoptotic response to ER stress, revealing—to our knowledge—the first bona fide apoptotic defect linked to Bok deletion.BAX and BAK are essential B-cell lymphoma-2 (BCL-2) family proteins that porate the mitochondrial outer membrane in response to a broad range of apoptotic stimuli (1). BCL-2 ovarian killer (BOK) exhibits ∼70–80% sequence homology to BAX and BAK, sharing BH1-3 domains and a carboxy-terminal transmembrane domain (2). Like BAX and BAK, BOK is widely expressed and induces cell death upon transient overexpression (2–9). In the context of BOK overexpression, BOK-induced cell death manifests classical apoptotic features, including the release of cytochrome c, activation of caspase-3, and nuclear and DNA fragmentation (6, 9–11). In addition, overexpression of antiapoptotic MCL-1, BFL-1/A1, and BHRF-1 inhibit BOK-mediated cell death (2, 7, 12, 13). Based on these similarities, it has been suggested that BOK acts in a redundant fashion to BAX and BAK and may be responsible for the apparently normal development of numerous organs in Bax^−/−Bak^−/− mice (14).Despite these initial observations, the physiologic role of BOK in responding to cell stress has remained enigmatic. Indeed, the development and characterization of Bok-deficient mice revealed little to no phenotype (3). Moreover, leukocyte subsets from Bok^−/− mice showed no alteration in their death response to classical proapoptotic agents, such as etoposide, dexamethasone, Fas ligand, ABT-737, or cytokine deprivation (3). Even Bok^−/−Bax^−/− and Bok^−/−Bak^−/− doubly deficient mice are mostly normal, and cells derived from these mice are equally susceptible to death stimuli (15), in stark contrast to the severe apoptotic blockade of Bax^−/−Bak^−/− cells. Also intriguing, a functional role for Bok as a tumor suppressor was suggested by its genetic location in 1 of the 20 most deleted regions in all human cancers (16).To investigate a role for BOK in the apoptotic pathway, we generated Bok^−/− mice and cells. Based on the recent localization of BOK at the endoplasmic reticulum (ER) (4), we focused our inquiry on ER stress pathways, including the unfolded protein response (UPR). We find that Bok^−/− cells manifest reduced activation of the classical mitochondrial apoptotic pathway in response to a battery of ER stress stimuli. Moreover, the apoptotic deficiency is selective, with no observed differences in response to other inducers of apoptosis. From a mechanistic standpoint, we find that BOK requires downstream BAX/BAK activation to induce mitochondrial apoptosis, as BOK expression can rescue the defective response of Bok^−/− cells, but not Bax^−/−Bak^−/− cells. These findings support a selective role for BOK in regulating the apoptotic response to ER stress, a functional activity that corresponds to its recent subcellular localization at the ER.     

血管平滑肌细胞内质网应激与血管钙化的研究进展

血管钙化是指羟基磷灰石沉积于血管壁,由多因素参与及调控,类似于骨、软骨形成的主动生物学过程。内质网应激是机体内适应性调节反应,适当的内质网应激帮助维持内质网稳态,但过度的内质网应激会促进血管钙化的发生与发展。本文综述内质网应激尤其是未折叠蛋白反应在血管钙化中的潜在作用和分子机制,希望为血管钙化的防治提供新的思路。     

内质网应激在酒精性肝病发病中的作用

内质网应激（ERS）是细胞内质网内稳态失衡和生理功能紊乱的一种病理状态。从已有的文章报道总结出多种导致机体功能紊乱的因素均可引起ERS和非折叠蛋白反应（UPR）。根据近年来研究,得出ERS参与酒精性肝损伤的发病,并在其中发挥重要作用。     

内质网应激在慢性阻塞性肺疾病中的研究进展

内质网应激(ERS)是细胞的一种重要自我防御机制,而强烈持久的ERS可导致细胞凋亡。未折叠蛋白反应是ERS的一条重要信号通路。支气管、肺泡上皮等细胞内含多种蛋白质合成分泌旺盛的细胞类型,本身易出现ERS;目前认为ERS与慢性阻塞性肺疾病(COPD)发病机制有一定关系。本文即对ERS与COPD的相关研究作一综述,希望为COPD的治疗提供新的方向。