内质网应激与动脉粥样硬化的研究进展

内质网应激是指细胞在缺血、氧化应激、钙稳态紊乱、蛋白质折叠错误或正常蛋白质表达增强等条件下发生的一系列适应性的保护反应。越来越多的研究表明,内质网应激在动脉粥样硬化发展的所有阶段均具有重要作用。该文主要综述了动脉管壁不同类型的细胞中内质网应激和细胞凋亡在动脉粥样硬化发展中的作用,并总结了目前调节这些途径的靶向分子以及它们在动脉粥样硬化治疗中的潜在疗效。     

内质网应激与心血管疾病关系的研究进展

内质网是蛋白质折叠、转录后修饰和转运的重要细胞器,对维持细胞稳态具有重要作用。多种内外环境刺激能够引起内质网内错误折叠或未折叠蛋白的积累,即形成内质网应激。内质网应激激活未折叠蛋白反应(unfolded protein response,UPR),进而启动一系列下游信号以维持内质网稳态。但持续或过度的内质网应激激活的UPR最终导致细胞凋亡和疾病。近年来,大量研究证据表明,内质网应激参与多种心血管疾病(cardiovascular disease, CVD)的发生和发展,包括缺血性心脏病、糖尿病性心肌病、心力衰竭、动脉粥样硬化、血管钙化、高血压和主动脉瘤等,是治疗多种CVD的重要靶点。本文就内质网应激激活UPR在多种常见CVD中的调控机制以及内质网应激与CVD关系的研究进展作一简要综述。     

内质网应激在胰岛素抵抗中的作用

2型糖尿病正成为日益突出的世界性健康问题。胰岛素抵抗在2型糖尿病的发病中起到了重要的促进作用。近年来,很多研究发现,内质网应激与胰岛素抵抗具有密切的联系。内质网应激不仅是胰岛素信号通路的直接负调节因素,还可通过多种方式作用于不同靶组织促进胰岛素抵抗。该文就内质网应激与胰岛素抵抗在2型糖尿病发病中的作用机制及可能的靶向治疗策略作一综述。     

转录激活因子6：潜在的抗2 型糖尿病药物新靶点

真核细胞中的内质网是蛋白质合成、翻译和转运的场所,当内质网稳态被打破,出现蛋白质折叠障碍或错误折叠,并导致蛋白质过度积累时,便会引发内质网应激反应,即未折叠蛋白反应。大量的研究表明,内质网应激与2 型糖尿病的病理特征有一定的关系,而转录激活因子6 通路作为未折叠蛋白反应中3 条信号通路之一,调控着蛋白质的重折叠过程,对缓解内质网应激以及在糖脂代谢和胰岛素敏感性方面起着重要作用。简介内质网应激反应及相关信号通路和转录激活因子6,着重综述转录激活因子6 在肝脏糖脂代谢和胰岛素抵抗中的作用及相应机制,探讨其成为抗2 型糖尿病药物新靶点的可能性,为抗2 型糖尿病药物的研发提供新思路。     

2型糖尿病血管内皮损伤与内质网应激

本文对内质网应激与2型糖尿病血管内皮损伤的关系进行综述。糖尿病已成为21世纪世界范围内的一种流行病,内质网应激不仅参与了糖尿病的发病机制,同时也在其心血管并发症的发生中起着重要作用。研究发现血管内皮的损伤是其并发症的基本机制。高血糖能引发内质网应激直接造成内皮损伤,而内质网应又可激通过炎症反应间接损伤内皮,所以保护内质网功能成为了一种可能的治疗方案。     

内质网应激在肾脏疾病进展中的作用

内质网应激是机体对有害刺激的一种自身应答机制,细胞是存活还是死亡取决于刺激信号的强弱,适宜的内质网应激可保护细胞免受各种刺激的损害作用,而过强或过长时间的内质网应激使保护机制不能与损伤抗衡则扰乱内质网稳态,诱导细胞凋亡发生。内质网应激作为多种应激过程的共同通路,与多种肾脏疾病的进展密切相关,例如:肾小球疾病、肾小管间质损伤、肾缺血再灌注损伤、糖尿病肾病等。本文就内质网应激在肾脏疾病进展中作用的研究进展作一综述。     

内质网应激与自噬及其交互效应:动脉粥样硬化潜在的治疗新靶标

持续的内质网应激是导致细胞凋亡和继发的组织功能障碍的重要病理机制之一。在氧化应激、高同型半胱氨酸、高胆固醇水平及胰岛素抵抗等情况下,未折叠蛋白反应会被持续过度激活,促进动脉粥样硬化的发生发展。自噬是细胞自我更新,维持内环境稳态,同时调节营养代谢的重要方式之一。近年来研究表明,内质网应激、细胞自噬及其交互效应在动脉粥样硬化形成及发展中扮演了重要角色,内质网应激、细胞自噬及其交互作用是未来治疗动脉粥样硬化性疾病的新靶标。     

内质网应激及线粒体功能障碍在糖尿病血管内皮损伤中作用的研究进展

血管内皮损伤是糖尿病血管并发症的起始环节,涉及多种机制,氧化应激被认为其中关键的环节,但补充外源性抗氧化剂的治疗目前仍存在争议。内质网及线粒体是参与细胞内活性氧生成的关键细胞器,探讨内质网应激、线粒体功能障碍及氧化应激之间的相互关系可能对于阐明糖尿病相关血管内皮功能障碍的发病机制有重要的意义。本文综述了近年关于内质网及线粒体功能障碍在糖尿病相关血管并发症中的研究进展并分析了二者的相互作用在氧化应激中的重要作用。     

血管内皮细胞内质网应激

内质网是调控细胞内膜型/分泌型蛋白质合成、钙稳态和细胞凋亡的重要细胞器,多种因素影响内质网稳态、触发内质网应激。适当的内质网应激通过激活未折叠蛋白反应促进内质网紊乱的恢复,但过度内质网应激触发内质网相关凋亡途径,参与多种疾病的发生。血管内皮细胞具有高度发达的内质网,对内质网应激非常敏感,本文综述血管内皮细胞内质网应激反应及其在血管损伤相关疾病中的作用。     

自噬与内质网应激的相互关系及其在动脉粥样硬化发展和防治中的作用

自噬是细胞将受损蛋白质及细胞器运输至溶酶体进行消化降解的过程,是细胞维持内环境稳定的重要防御机制之一。近年来研究表明自噬在动脉粥样硬化病变中活性增强并参与其发病过程。氧化脂质、细胞因子及晚期糖基化终产物均可激活自噬,后者在动脉粥样硬化进展过程中发挥着保护或损伤性作用。然而自噬在动脉粥样硬化发展的不同阶段确切的作用及机制尚未完全阐明。本文总结了近年来有关血管细胞中的自噬反应及其在动脉粥样硬化发展中的作用研究进展,并讨论了自噬与内质网应激之间的相互关系以及自噬是否可作为动脉粥样硬化防治的新靶点。     

内质网应激及其在糖尿病肾病中的作用机制

糖尿病肾病（diabetic nephropathy,DN）是糖尿病最常见的微血管并发症,是导致终末期肾脏疾病（end-stage renal disease,ESRD）的继发性肾脏疾病的主要病因之一。多种因素如缺氧、氧化应激、病毒感染、遗传突变等,可导致内质网内稳态失衡,大量未折叠蛋白和错误折叠引起蛋白堆积,即形成内质网应激(endoplasmic reticulum stress, ERS),从而激活未折叠蛋白反应(unfolded protein response, UPR)介导的三条经典的细胞适应性应答通路以恢复内质网稳态和细胞活性。但如果刺激过强或持续存在,便会启动细胞凋亡信号通路。大量研究表明ERS与DN的发生发展相关,并参与不同类型肾细胞损伤的过程,因此ERS作为治疗DN的有效靶点具有很重要的研究前景,调控ERS可为DN的治疗提供新的理论支持。从ERS相关信号通路及其在DN中的作用和新进展领域作一综述,以期为DN的治疗研究提供参考。     

GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.     

Emerging Piezo1 signaling in inflammation and atherosclerosis; a potential therapeutic target

Purpose of Review: Atherosclerosis is the principal cause of cardiovascular diseases (CVDs) which are the major cause of death worldwide. Mechanical force plays an essential role in cardiovascular health and disease. To bring the awareness of mechanosensitive Piezo1 role in atherosclerosis and its therapeutic potentials we review recent literature to highlight its involvement in various mechanisms of the disease.Recent Findings: Recent studies reported Piezo1 channel as a sensor, and transducer of various mechanical forces into biochemical signals, which affect various cellular activities such as proliferation, migration, apoptosis and vascular remodeling including immune/inflammatory mechanisms fundamental phenomenon in atherogenesis.Summary: Numerous evidences suggest Piezo1 as a player in different mechanisms of cell biology, including immune/inflammatory and other cellular mechanisms correlated with atherosclerosis. This review discusses mechanistic insight about this matter and highlights the drugability and therapeutic potentials consistent with emerging functions Piezo1 in various mechanisms of atherosclerosis. Based on the recent works, we suggest Piezo1 as potential therapeutic target and a valid candidate for future research. Therefore, a deeper exploration of Piezo1 biology and translation towards the clinic will be a novel strategy for treating atherosclerosis and other CVDs.     

Chemerin及ChemR23与糖尿病大血管病变

Chemerin是2007年新确认的一种脂肪因子,其主要功能受体为ChemR23。近期研究发现chemerin可能是联系肥胖、糖尿病及动脉粥样硬化的潜在因子,有望为糖尿病及其血管并发症的预防及治疗提供新的靶点。然而,chemerin及其受体ChemR23参与糖尿病及其大血管病变的具体机制尚不明确。本文将就目前研究中chemerin及其受体ChemR23与糖尿病及其大血管病变的关系作一综述,并从免疫及炎症反应、氧化应激、自噬、糖脂代谢和胰岛素抵抗等方面,分析chemerin分别对巨噬细胞、血管内皮细胞、脂肪细胞及骨骼肌细胞的影响,从而进一步阐述chemerin及其受体ChemR23参与糖尿病及其大血管病变的具体生物学机制。     

Free Fatty Acid Induces Endoplasmic Reticulum Stress and Apoptosis of β-cells by Ca2+/Calpain-2 Pathways

Dysfunction of β-cells is a major characteristic in the pathogenesis of type 2 diabetes mellitus (T2DM). The combination of obesity and T2DM is associated with elevated plasma free fatty acids (FFAs). However, molecular mechanisms linking FFAs to β-cell dysfunction remain poorly understood. In the present study, we identified that the major endoplasmic reticulum stress (ERS) marker, Grp78 and ERS-induced apoptotic factor, CHOP, were time-dependently increased by exposure of β-TC3 cells to FFA. The expression of ATF6 and the phosphorylation levels of PERK and IRE1, which trigger ERS signaling, markedly increased after FFA treatments. FFA treatments increased cell apoptosis by inducing ERS in β-TC3 cells. We also found that FFA-induced ERS was mediated by the store-operated Ca²⁺ entry through promoting the association of STIM1 and Orai1. Moreover, calpain-2 was required for FFA-induced expression of CHOP and activation of caspase-12 and caspase-3, thus promoting cell apoptosis in β-TC3 cells. Together, these results reveal pivotal roles for Ca²⁺/calpain-2 pathways in modulating FFA-induced β-TC3 cell ERS and apoptosis.     

内质网应激与哺乳动物雄性生殖

内质网应激 (endoplasmic reticulum stress,ERS) 激活未折叠蛋白反应,维持哺乳动物细胞的胞内稳态,过度持续的ERS导致细胞凋亡。最新研究表明,ERS对哺乳动物雄性生殖有重要的调节作用,包括对精母细胞、睾丸结构及精子发生的影响。ERS是研究生殖细胞生存和凋亡的新通路。雄性不育可能是由过度ERS引起的。本文通过简述ERS的最新研究进展,分析雄性生殖与ERS的关系,并从ERS调控雄性生殖角度提出新的理解和展望。     

High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease

PURPOSE OF REVIEW: Low HDL-cholesterol, diabetes mellitus and elevated C-reactive protein as well as various inflammatory diseases are risk factors for coronary heart disease. Both diabetes mellitus and inflammation decrease HDL-cholesterol. We summarize recent findings on the mechanisms underlying low HDL-cholesterol in diabetes and inflammation, as well as on novel functions of HDL that may protect not only from atherosclerosis but also from diabetes mellitus and inflammation-induced organ damage. RECENT FINDINGS: Elevated levels of non-esterified fatty acids and disturbed insulin action contribute to low HDL-cholesterol in diabetes mellitus by modifying lipolysis, apolipoprotein A-I production, as well as the activities of adenosine triphosphate-binding cassette transporter A1 and lipid transfer. Inflammation causes low HDL-cholesterol by increasing the activities of endothelial lipase and soluble phospholipase A2 and by replacing apolipoprotein A-I in HDL with serum amyloid A. HDL and lysosphingolipids therein have been identified as activators of the protein kinase Akt, which in turn is a regulator of apoptosis in beta-cells, endothelial cells, and smooth muscle cells, as well as a regulator of nitric oxide production and adhesion molecule expression in endothelial cells. SUMMARY: The protective properties of HDL in cytokine production, lipid oxidation, cholesterol efflux and reverse cholesterol transport make HDL a protective agent in inflammation-induced organ damage including diabetes mellitus. However, inflammation and diabetes cause a decrease in HDL-cholesterol concentrations and impair HDL function, placing HDL into the centre of a vicious cycle that may escalate into diabetes mellitus, inflammation-induced organ damage and atherosclerosis.     

Chronic hyperglicemia and nitric oxide bioavailability play a pivotal role in pro-atherogenic vascular modifications

Diabetes is associated with accelerated atherosclerosis and macrovascular complications are a major cause of morbidity and mortality in this disease. Although our understanding of vascular pathology has lately greatly improved, the mechanism(s) underlying enhanced atherosclerosis in diabetes remain unclear. Endothelial cell dysfunction is emerging as a key component in the pathophysiology of cardiovascular abnormalities associated with diabetes. Although it has been established that endothelium plays a critical role in overall homeostasis of the vessels, vascular smooth muscle cells (vSMC) in the arterial intima have a relevant part in the development of atherosclerosis in diabetes. However, high glucose induced alterations in vSMC behaviour are not fully characterized. Several studies have reported that impaired nitric oxide (NO) synthesis and/or actions are often present in diabetes and endothelial dysfunction. Furthermore, although endothelial cells are by far the main site of vascular NO synthesis, vSMC do express nitric oxyde synthases (NOSs) and NO synthesis in vSMC might be important in vessel's function. Although it is known that vSMC contribute to vascular pathology in diabetes by their change from a quiescent state to an activated proliferative and migratory phenotype (termed phenotypic modulation), whether this altered phenotypic modulation might also involve alterations in the nitrergic systems is still controversial. Our recent data indicate that, in vivo, chronic hyperglycemia might induce an increased number of vSMC proliferative clones which persist in culture and are associated with increased eNOS expression and activity. However, upregulation of eNOS and increased NO synthesis occur in the presence of a marked concomitant increase of O(2-) production. Since NO bioavailabilty might not be increased in high glucose stimulated vSMC, it is tempting to hypothesize that the proliferative phenotype observed in cells from diabetic rats is associated with a redox imbalance responsible quenching and/or trapping of NO, with the consequent loss of its biological activity. This might provide new insight on the mechanisms responsible for accelerated atherosclerosis in diabetes.