内质网应激与动脉粥样硬化的研究进展

内质网(ER)是真核细胞复杂的膜结构,参与蛋白质折叠、脂质合成,调节细胞Ca2+摄取、储存和信号传导,并参与细胞脂质的产生。内质网蛋白质折叠能力可以达到饱和,从而诱导内质网应激(ERS)反应。越来越多的证据表明,在动脉粥样硬化病变的病理条件下,ERS与细胞凋亡和炎症有关,并有助于动脉粥样硬化的进展。ERS在动脉粥样硬化病变中不同类型细胞中的作用,包括长期ERS诱导的凋亡和炎症途径的激活,尤其是在晚期病变巨噬细胞和内皮细胞(ECs)中,以及不同病变细胞中常见的动脉粥样硬化相关内质网应激源,都有助于动脉粥样硬化的临床进展。鉴于ERS和未折叠蛋白反应(UPR)信号通路在动脉粥样硬化和心血管疾病中的重要作用,针对这些过程来减轻ERS可能是一种新的治疗策略。     

动脉粥样硬化中炎性反应与内质网应激的相互作用

炎性反应和内质网应激均是动脉粥样硬化发生和发展过程中的重要事件。炎性反应可通过多条途径诱发内质网应激,而内质网应激在疾病的不同阶段可抑制或者促进炎性反应。     

内质网应激与心血管疾病

内质网应激是细胞内一种适应性机制,持续或过强的内质网应激则诱导细胞凋亡,造成组织损伤.多项研究显示内质网应激是多种心血管疾病如动脉粥样硬化、缺血性心脏病、心肌肥大、心力衰竭及糖尿痛心肌病等发生、发展的共同通路,干预内质网应激可能成为心血管疾病治疗的新靶点.     

动脉粥样硬化中炎性反应与内质网应激的相互作用简

 炎性反应和内质网应激均是动脉粥样硬化发生和发展过程中的重要事件。炎性反应可通过多条途径诱发内质网应激，而内质网应激在疾病的不同阶段可抑制或者促进炎性反应。     

钙联蛋白调控内质网应激诱导的细胞凋亡

内质网应激(ERS)可诱导多种细胞凋亡,与疾病发生发展密切相关.钙联蛋白(CNX)是内质网中重要的类凝集素分子伴侣,通过参与未折叠蛋白反应募集凋亡相关因子、激活IRE1-JNK激酶等途径,调控ERS诱导的凋亡.本文就其研究现状进行阐述.     

Ca2+与内质网途径的细胞凋亡

细胞Ca2+稳态的维持主要是通过内质网进行的，Ca2+在细胞内的活动多与内质网有关，胞内\[Ca2+\]的变化可以引起内质网应激，而过度的内质网应激则会导致细胞的凋亡。由于内质网和线粒体在细胞内空间结构上的接近，内质网释放的Ca2+又会引起线粒体途径的凋亡。一些内质网相关的因素也参与Ca2+所引起的细胞内质网途径的凋亡。     

内质网应激与细胞凋亡

内质网（ER）是细胞内重要的细胞器,参与多种细胞进程,这些进程对于维持细胞存活和发挥细胞的正常生理功能具有重要的作用。然而在多种生理病理条件下,内质网稳态会发生变化而失衡,从而诱发内质网应激（ERS）,此时机体通过激活未折叠蛋白反应（UPR）来恢复内质网的正常功能。当持续的ERS状态无法恢复时,ERS就会触发细胞凋亡程序,通过不同的凋亡途径引起细胞凋亡。     

巨噬细胞凋亡研究的若干进展

巨噬细胞是机体免疫系统的重要细胞成份 ,具有多种生理功能 ,并参与清除入侵致病微生物 ,杀伤肿瘤细胞 ,而且在动脉粥样硬化、高血压等心血管疾病的发生发展中具有重要意义。本文综述了近年来巨噬细胞凋亡研究的若干进展 ,包括巨噬细胞凋亡在形态学和生化学上的主要改变 ,以及常见的诱导因素和相关基因 ,并初步探讨了巨噬细胞凋亡在动脉粥样硬化病变中的意义     

以内质网应激浅谈糖尿病及其并发脑病的研究进展

研究表明,内质网应激（ERS）在糖尿病及糖尿病脑病发病中起着重要作用。结果发现,内质网应激介导的胰岛B细胞凋亡参与了糖尿病的发生,糖尿病脑病小鼠海马组织内发生了内质网应激。内质网应激在糖尿病及其并发糖尿病脑病的发病机制地研究与治疗方法地改善中具有广泛的应用前景和社会效益。     

内质网应激参与糖脂毒性引起的胰岛β细胞凋亡

 胰岛β细胞具有高度发达的内质网,是对内质网应激最敏感的细胞之一。高浓度的游离脂肪酸引起内质网应激反应进而诱导了β细胞的凋亡,葡萄糖则促进了脂肪酸通过内质网应激引起的β细胞凋亡。总之,内质网应激介导了糖脂毒性引起的β细胞凋亡。     

Class A scavenger receptor activation inhibits endoplasmic reticulum stress-induced autophagy in macrophage

Macrophage death in advanced atherosclerosis promotes plaque necrosis and destabilization. Involvement of autophagy in bulk degradation of cellular components has been recognized recently as an important mechanism for cell survival under endoplasmic reticulum (ER) stress. We previously found that the engagement of class A scavenger receptor (SR-A) triggered JNK-dependent apoptosis in ER-stressed macrophages. However, pro-apoptotic mechanisms mediated by SR-A are not fully understood. Therefore, we sought to see if SR-A mediated apoptosis was associated with autophagy in macrophages. Here, we showed that fucoidan inhibited microtubule-associated protein light chain 3-phospholipid conjugates (LC3-II) formation as well as the number of autophagosomes under ER stress. The inhibition of LC3-II formation was paralleled by the activation of the mTOR pathway, and the inhibition of mTOR allowed LC3-II induction in macrophages treated with thapsigargin plus fucoidan. Furthermore, apoptosis induced by fucoidan was prevented under ER stress by the mTOR inhibitor. We propose that fucoidan, a SR-A agonist, may contribute to macrophage apoptosis during ER stress by inhibiting autophagy.     

A VLP‐based vaccine against interleukin‐1α protects mice from atherosclerosis

Interleukin (IL)‐1α is a potent proinflammatory cytokine that has been implicated in the development of atherosclerosis. We investigated whether a vaccine inducing IL‐1α neutralizing antibodies could interfere with disease progression in a murine model of atherosclerosis. We immunized Apolipoprothin E (ApoE)‐deficient mice with a vaccine (IL‐1α‐C‐Qβ) consisting of full‐length, native IL‐1α chemically conjugated to virus‐like particles derived from the bacteriophage Qβ. ApoE^?/? mice were administered six injections of IL‐1α‐C‐Qβ or nonconjugated Qβ over a period of 160 days while being maintained on a western diet. Atherosclerosis was measured in the descending aorta and in cross‐sections at the aortic root. Macrophage infiltration in the aorta was measured using CD68. Expression levels of VCAM‐1, ICAM‐1, and MCP‐1 were quantified by RT‐PCR. Immunization against IL‐1α reduced plaque progression in the descending aorta by 50% and at the aortic root by 37%. Macrophage infiltration in the aorta was reduced by 22%. Inflammation was also reduced in the adventitia, with a decrease of 54% in peri‐aortic infiltrate score and reduced expression levels of VCAM‐1 and ICAM‐1. Active immunization targeting IL‐1α reduced both the inflammatory reaction in the plaque as well as plaque progression. In summary, vaccination against IL‐1α protected ApoE^?/? mice against disease, suggesting that this may be a potential treatment option for atherosclerosis.     

Nogo‐B expression,in arterial intima,is impeded in the early stages of atherosclerosis in humans

Nogo‐B (Reticulon 4B) is considered to be a novel vascular marker, which may have a protective role in injury‐induced neointima formation and atherosclerosis. Nogo A/B is found to be crucial for monocyte/macrophage recruitment in acute inflammation and it is expressed in CD68 + macrophages. We hypothesize that macrophage infiltration in atherosclerosis is not dependent on Nogo‐B expression in arterial wall. We have assessed Nogo‐B expression and macrophage accumulation in the iliac arteries of healthy organ donors and organ donors with cardiovascular risk factors. Paraffin sections of 66 iliac arteries, from 44 deceased organ donors (17 women and 27 men), were studied. The healthy and cardiovascular risk (CVR) subgroups were created. With regard to staging of the atherosclerotic process, the thickness of arterial intima was measured in digitalized images of H+E stained tissue sections. Immunohistochemical reactions (Nogo‐B and CD68) were carried out in all arteries (66 samples). Western blotting (WB‐19 samples) and real‐time PCR (27 samples) were performed on selected arteries. Significantly higher Nogo‐B expression was demonstrated in the intima of the healthy subjects' subgroup, using immunohistochemistry. WB and real‐time PCR revealed a trend toward lower Nogo‐B expression in the adventitia of the CVR subgroup. Furthermore, the thickness of the intima was found to negatively correlate with the expression of Nogo‐B in the intima and media (r = ?0.32; p < 0.05; r = ?0.32; p < 0.05). Macrophage infiltrates were more prominent in intima of CVR subjects (0.65 vs 3.52 a.u.; p < 0.01). Macrophage density in intima increased with atherosclerosis progression (r = 0.37; p < 0.01). CD68 macrophages density in adventitia was lower in CVR arteries than in healthy arteries. The expression of Nogo‐B, in arterial intima, is impeded in the early stages of atherosclerosis. Accumulation of arterial intimal CD68 macrophages has been shown to progress; however, the overall macrophage density in the adventitia is reduced in arteries shown to have intimal thickening. Macrophage infiltration is not accompanied by Nogo‐B expression in atherosclerotic arteries.     

Multifunctional roles of macrophages in the development and progression of atherosclerosis in humans and experimental animals

In atherosclerosis, macrophages are important for intracellular lipid accumulation and foam cell formation. Monocytes respond to chemotactic factors, cytokines, and macrophage growth factors produced by vascular endothelial cells, smooth muscle cells, and infiltrated cells, by migrating from peripheral blood into the arterial intima and differentiating into macrophages in atherosclerotic lesions. Although various chemotactic factors are known to induce monocyte migration, monocyte chemoattractant protein-1 is the most important and powerful inducer of migration into atherosclerotic lesions. Macrophage colony-stimulating factor is crucial for monocyte/macrophage differentiation and proliferation, and for the survival of macrophages in these lesions. A minor population of macrophages can proliferate in the atherosclerotic lesions themselves, particularly in the early stage. The macrophages express a variety of receptors, particularly scavenger receptors, and take up modified lipoproteins, including oxidized low-density lipoprotein, beta-very-low-density lipoprotein, and/or enzymatically degraded low-density lipoprotein. These cells accumulate cholesterol esters in the cytoplasm, which leads to foam cell formation in lesion development. Among various scavenger receptors, class A type I and type II macrophage scavenger receptors (MSR-A I,II) play the most important role in the uptake of oxidized low-density lipoprotein by macrophages. In addition, macrophages and macrophage-derived foam cells produce ceroid and advanced glycation end-products (AGEs) and accumulate these substances in their cytoplasm. Extracellularly generated AGEs are taken up by macrophages via receptors for AGEs, including MSR-AI,II. Most foam cells die in loco because of apoptosis, and some foam cells escape from the lesions into peripheral blood. Macrophages also play multifaceted roles in inducing plaque rupture, blood coagulation, and fibrinolysis via the production of various enzymes, activators, inhibitors, and bioactive mediators. During the development of atherosclerosis, macrophages interact with vascular endothelial cells, medial smooth muscle cells, and infiltrated inflammatory cells, particularly T cells and dendritic cells. This review, based on data accumulated in studies of atherosclerosis in humans and experimental animals, focuses on the multifunctional roles of macrophages in the pathogenesis and progression of atherosclerosis.     

Structural features of cell death in atherosclerotic lesions affecting long-term aortocoronary saphenous vein bypass grafts

Aortocoronary saphenous vein bypass grafts fail because of structural pathologies (thrombosis, intimal hyperplasia and atherosclerosis) within the 'arterialized' vein leading to graft stenosis. This study examined structural characteristics of atherosclerotic alterations in long-term aortocoronary artery saphenous vein bypass grafts with particular attention to the features of cell death in atherosclerotic lesions. Stenotic vein grafts were obtained from 10 patients at redo coronary artery bypass grafting operations. All the grafts were affected by histological abnormalities, with eight out of ten grafts showing evidence of atherosclerotic alterations in the intimal hyperplastic layer. Areas containing foam cells were examined by electron microscopy. Cells with cytoplasmic lipid accumulations were characterized by varying degrees of chromatin condensation, fragmentation or dispersion, by focal areas of oedema and vacuolisation of their cytoplasm, and by plasmalemmal destruction. Some lipid-filled cells exhibiting signs of destruction contained myofilaments and basal membrane fragments, allowing them to be identified as smooth muscle cells. Macrophage foam cells were found to have undergone similar destruction. No cells showing nuclear degeneration were observed to have intact cytoplasmic organelles. Neither were apoptotic bodies identified, but necrotic remnants were frequently seen. The results suggest that cell death in atherosclerotic lesions affecting aortocoronary artery saphenous vein bypass grafts occurs through oncosis rather than by apoptosis.     

Salmonella enterica serovars Typhimurium and Dublin can lyse macrophages by a mechanism distinct from apoptosis

Salmonella enterica serovars Typhimurium and Dublin lysed primary bovine alveolar macrophages and immortalized J774.2 macrophage-like cells in the absence of either the morphological changes or DNA fragmentation characteristic of apoptosis. Macrophage lysis was dependent on a subset of caspases and an intact sipB gene.     

Effect of macrophage colony stimulating factor overexpression on oxidative injury/resistance of RAW264.7 cells

Oxidative injury to monocytes/macrophages is considered one of the key factors in atherogenesis. Macrophage colony stimulating factor (M-CSF) also plays an important role in the stages of atherosclerosis. Some researchers showed that M-CSF accelerated pathological changes in the early stages of atherosclerosis. However, other reports suggested that exogenous M-CSF could prevent the progress of atherosclerosis. To further investigate the role of M-CSF in atherogenesis and to elucidate the effect of M-CSF on the oxidative injury to monocytes/macrophages, RAW264.7 cell lines overexpressing M-CSF were established by applying the lipofectin transfection method. The oxidative injurious effect of tert-butylhydroperoxide on the established cell lines was investigated. Two M-CSF-transfected RAW264.7 cell lines secreted large amounts of M-CSF. Compared with the non-transfected RAW264.7 cells, M-CSF-overexpressing RAW264.7 cells were more vulnerable to oxidative injury. We conclude that M-CSF could aggravate the oxidative injury due to macrophages in some situations. Received: 21 August 2002 / Accepted: 12 March 2003 Correspondence to Z.-J. Pang     

In atherogenesis, the apoptosis of endothelial cell itself could directly induce over-proliferation of smooth muscle cells

Over-proliferation of SMC (smooth muscle cell) is one characteristics of atherosclerosis. One well accepted mechanism is that the decrease of ECs (endothelial cells) induced by over apoptosis leads to endothelial dysfunction, which in turn results in over-proliferation of SMC. Obviously, the mechanism works after endothelial apoptosis. Compared with necrosis, apoptosis is time and energy consuming. The question is why the cell ends in the form of apoptosis instead of necrosis. From the evolutionary standpoint, apoptosis has some useful functions other than removing the damaged or unwanted cells. Recent studies showed that cells nearby the apoptotic ones began to proliferate and differentiate before apoptosis and the apoptotic signals could induce the near cells to proliferate without the death of cells. Apparently, some mechanism in apoptosis results in the proliferation of cells. So, we hypotheses that endothelial apoptosis can directly induce the over-proliferation of SMC.     

Stimulation of vascular smooth muscle cell migration by macrophage migration inhibitory factor

Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor that influences the migration and proliferation of various cell types, predominantly monocytes and macrophages. Recent evidence suggests an important role for MIF in the progression of atherosclerosis and restenosis. For this reason, we studied the effect of MIF on platelet-derived growth factor-BB (PDGF-BB)-induced migration and PDGF receptor protein expression in vascular smooth muscle cells (VSMCs). Furthermore, the possibility of MIF influencing the migration of VSMCs was investigated. Our results show that short-term incubation of MIF is able to enhance PDGF-BB-induced migration. Long-term incubation decreases PDGF-BB-induced migration, but preserves a short-term stimulatory effect. These effects are not regulated at the level of PDGF receptor protein expression. MIF also acts as a chemoattractant for VSMCs, with a maximum response at 15 ng/ml. In contrast, the proliferation of VSMCs was unaffected by MIF. We conclude that MIF has a biphasic effect on VSMC migration. It remains unclear whether this effect is direct or involves the secretion of unidentified promigratory factors. Exogenous MIF does not stimulate VSMC proliferation; however, a role for MIF in proliferation cannot be fully ruled out. In view of the known key contributions of macrophage-derived MIF and VSMCs, the observed effects may well play a role in the progression of atherosclerosis and restenosis.