Regulatory T cell responses: potential role in the control of atherosclerosis

PURPOSE OF REVIEW: Atherosclerosis is an inflammatory disease of the arterial wall where both innate and adaptive Th1-driven immunoinflammatory responses contribute to disease development. Th2-related responses have been shown to be either protective or pathogenic. Thus, it is unclear whether immunoregulatory activity can modulate disease development. RECENT FINDINGS: Novel subtypes of T cells, called the regulatory T cells, have been shown recently to play a critical role in the maintenance of immunological tolerance against self and non-self antigens and prevent the development of various immunoinflammatory diseases. Preliminary studies suggest a potential role for this type of regulatory T cell response in atherosclerosis. SUMMARY: Here we present a novel view of the immunoinflammatory response in atherosclerosis where natural and/or adaptive regulatory T cell responses modulate both Th1 and Th2 pathogenic responses and play a central role in counteracting disease initiation and progression.     

Heat shock proteins in hematopoietic malignancies

Inducible heat shock proteins are molecular chaperones whose expression is increased after many different types of stress. They have a protective function helping the cell to cope with lethal conditions. Their basal expression is low in nonstressed, normal and nontransformed cells. However, in cancer cells and particularly in hematological malignancies, they are surprisingly abundant. Malignant cells have to rewire their metabolic requirements and therefore have a higher need for chaperones. This cancer cell addiction for HSPs is the basis for the use of HSP inhibitors in cancer therapy. HSPs have been shown to interact with different key apoptotic proteins. As a result, HSPs can essentially block the apoptotic pathways at several steps, most of them involving the activation of cystein proteases called caspases. Apoptosis and differentiation are physiological processes that share many common features, for instance, a controlled caspase activation and chromatin condensation are frequently observed. It is, therefore, not surprising that HSPs may be implicated in the differentiation process. HSPs may determine the fate of the cells by orchestrating the decision of apoptosis versus differentiation. This review will focus on the role of HSPs in hematological malignancies and the emerging therapeutic options that are being either proposed or used to target these protective proteins.     

Are heat shock proteins therapeutic target for Parkinson's disease?

Heat shock proteins (HSPs), known as molecular chaperone to assist protein folding, have recently become a research focus in Parkinson's disease (PD) because the pathogenesis of this disease is highlighted by the intracellular protein misfolding and inclusion body formation. The present review will focus on the functions of different HSPs and their protective roles in PD. It is postulated that HSPs may serve as protein folding machinery and work together with ubiquitin-proteasome system (UPS) to assist in decomposing aberrant proteins. Failure of UPS is thought to play a key role in the pathogenesis of PD. In addition, HSPs may possess anti-apoptotic effects and keep the homeostasis of dopaminergic neurons against stress conditions. The critical role of HSPs and recent discovery of some novel HSPs inducers suggest that HSPs may be potential therapeutic targets for PD and other neurodegenerative disorders.     

昆虫的热休克反应和热休克蛋白

热休克（热激heatshock）是指短暂、迅速地向高温转换所诱导出的一种固定的应激反应。诱导该反应的温度在种与种之间有所不同。热休克反应最明显的特征是：伴随着正常蛋白质合成的抑制,一部分特殊蛋白质的诱导和表达增加,即为热休克蛋白（heatshockproteins,HSPs）。尽管热休克蛋白的合成也能被其它形式的应激反应所诱导,将它们认为是应激蛋白可能更恰当,但人们习惯上仍将这类蛋白质称为热休克蛋白。由于热休克反应和热休克蛋白是在果蝇（Drosophiliamelanogaster）中最初发现的,故在昆虫中,特别是果蝇等双翅目昆虫中研究得较深入…     

Regulatory role of vitamins E and C on extracellular matrix components of the vascular system

The protective effect of vitamins E (alpha-tocopherol) and C (L-ascorbic acid) in the prevention of cardiovascular disease (CVD) has been shown in a number of situations but a secure correlation is not universally accepted. Under certain conditions, both, L-ascorbic acid and alpha-tocopherol can exhibit antioxidant properties and thus may reduce the formation of oxidized small molecules, proteins and lipids, which are a possible cause of cellular de-regulation. However, non-antioxidant effects have also been suggested to play a role in the prevention of atherosclerosis. Vitamin E and C can modulate signal transduction and gene expression and thus affect many cellular reactions such as the proliferation of smooth muscle cells, the expression of cell adhesion and extracellular matrix molecules, the production of O(2)(-) by NADPH-oxidase, the aggregation of platelets and the inflammatory response. Vitamins E and C may modulate the extracellular matrix environment by affecting VSMC differentiation and the expression of connective tissue proteins involved in vascular remodeling as well as the maintenance of vascular wall integrity. This review summarizes individually the molecular activities of vitamins E and C on the cells within the connective tissue of the vasculature, which are centrally involved in the maintenance of an intact vascular wall as well as in the repair of atherosclerotic lesions during disease development.     

An introduction to biofluid mechanics--basic models and applications

Cardiovascular disease is the primary cause of morbidity and mortality in the western world. Complex hemodynamics play a critical role in the development of atherosclerosis and the processes of aging, as well as many other disease processes. Biofluid mechanics play a major role in the cardiovascular system and it is important to understand the forces and movement of blood cells and whole blood as well as the interaction between blood cells and the vessel wall. Fundamental fluid mechanical, which are important for the understanding of the blood flow in the cardiovascular circulatory system of the human body aspects are presented. Measurement techniques for model studies such as LDA, ultrasound, and MRI studies will be discussed. Viscosity and flow behavior changes specifically the creation of vortices and flow disturbances can be used to show how medication can influence flow behavior. Experiments have shown that hemodynamics may have a strong influence on the creation of aneurysms and varicose veins. Other factors such as vessel wall structure are also important. In preliminary studies, it has been demonstrated that geometry and elasticity of vessel walls help determine flow behavior. High velocity fluctuations indicate flow disturbances that should be avoided. Health care practitioners must understand fluid dynamic factors such as flow rate ratio, pressure and velocity gradients, and flow behavior, velocity distribution, shear stress on the wall and on blood cells. These mechanical factors are largely responsible for the deposit of blood cells and lipids, a leading cause of atherosclerosis. The interaction between blood cells and of the cells with the vessel, leads to the formation of plaques and agglomerations. These deposits are found predominantly at arterial bends and bifurcations where blood flow is disturbed, where a secondary flow is created, and where flow separation regions are found. Experiments on hemodynamic effects in elastic silicon rubber models of the cardiovascular system with flow wire, stents, or patches for vessel surgery will be discussed. These studies can be important in improving diagnostics and therapeutic applications.     

Th17细胞和Treg细胞与动脉粥样硬化

动脉粥样硬化从脂质条纹的形成到更复杂的病变和斑块破裂的进程是由多种不同类型的细胞和细胞因子网络共同参与作用的,其中最主要的是Th17细胞和Treg细胞及它们分泌的细胞因子。大量研究显示,Th17细胞对动脉粥样硬化的作用仍存在争议,但大部分研究仍认为其具有促动脉粥样硬化的作用。Treg细胞具有抗动脉粥样硬化的作用,Th17／Treg平衡对动脉粥样硬化的发生和发展具有重要的调节作用。本文将对Th17细胞、Treg细胞的生物学特性以及Th17细胞、Treg细胞和Th17／Treg平衡对动脉粥样硬化影响的最新研究进展做一综述。     

Heat shock proteins: essential proteins for apoptosis regulation

Many different external and intrinsic apoptotic stimuli induce the accumulation in the cells of a set of proteins known as stress or heat shock proteins (HSPs). HSPs are conserved proteins present in both prokaryotes and eukaryotes. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and stress-accumulated misfolded proteins, and by preventing their aggregation. HSPs have a protective function, that is they allow the cells to survive to otherwise lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several of these proteins have demonstrated to directly interact with components of the cell signalling pathways, for example those of the tightly regulated caspase-dependent programmed cell death machinery, upstream, downstream and at the mitochondrial level. HSPs can also affect caspase-independent apoptosis-like process by interacting with apoptogenic factors such as apoptosis-inducing factor (AIF) or by acting at the lysosome level. This review will describe the different key apoptotic proteins interacting with HSPs and the consequences of these interactions in cell survival, proliferation and apoptotic processes. Our purpose will be illustrated by emerging strategies in targeting these protective proteins to treat haematological malignancies.     

Baculovirus IE2 Stimulates the Expression of Heat Shock Proteins in Insect and Mammalian Cells to Facilitate Its Proper Functioning

Baculoviruses have gained popularity as pest control agents and for protein production in insect systems. These viruses are also becoming popular for gene expression, tissue engineering and gene therapy in mammalian systems. Baculovirus infection triggers a heat shock response, and this response is crucial for its successful infection of host insect cells. However, the viral protein(s) or factor(s) that trigger this response are not yet clear. Previously, we revealed that IE2-an early gene product of the baculovirus-could form unique nuclear bodies for the strong trans-activation of various promoters in mammalian cells. Here, we purified IE2 nuclear bodies from Vero E6 cells and investigated the associated proteins by using mass spectrometry. Heat shock proteins (HSPs) were found to be one of the major IE2-associated proteins. Our experiments show that HSPs are greatly induced by IE2 and are crucial for the trans-activation function of IE2. Interestingly, blocking both heat shock protein expression and the proteasome pathway preserved the IE2 protein and its nuclear body structure, and revived its function. These observations reveal that HSPs do not function directly to assist the formation of the nuclear body structure, but may rather protect IE2 from proteasome degradation. Aside from functional studies in mammalian cells, we also show that HSPs were stimulated and required to determine IE2 protein levels, in insect cells infected with baculovirus. Upon inhibiting the expression of heat shock proteins, baculovirus IE2 was substantially suppressed, resulting in a significantly suppressed viral titer. Thus, we demonstrate a unique feature in that IE2 can function in both insect and non-host mammalian cells to stimulate HSPs, which may be associated with IE2 stabilization and lead to the protection of the its strong gene activation function in mammalian cells. On the other hand, during viral infection in insect cells, IE2 could also strongly stimulate HSPs and ultimately affect viral replication.     

Apoptosis Versus Cell Differentiation: Role of Heat Shock Proteins HSP90, HSP70 and HSP27

Heat shock proteins HSP27, HSP70 and HSP90 are molecular chaperones whose expression is increased after many different types of stress. They have a protective function helping the cell to cope with lethal conditions. The cytoprotective function of HSPs is largely explained by their anti-apoptotic function. HSPs have been shown to interact with different key apoptotic proteins. As a result, HSPs can block essentially all apoptotic pathways, most of them involving the activation of cystein proteases called caspases. Apoptosis and differentiation are physiological processes that share many common features, for instance, chromatin condensation and the activation of caspases are frequently observed. It is, therefore, not surprising that many recent reports imply HSPs in the differentiation process. This review will comment on the role of HSP90, HSP70 and HSP27 in apoptosis and cell differentiation. HSPs may determine de fate of the cells by orchestrating the decision of apoptosis versus differentiation.Key Words: apoptosis, differentiation, heat shock proteins, chaperones, cancer cells, anticancer drugs     

The endothelial glycocalyx: a potential barrier between health and vascular disease

PURPOSE OF REVIEW: Although cardiovascular prevention has improved substantially, we still face the challenge of finding new targets to reduce the sequelae of atherosclerosis further. In this regard, optimizing the vasculoprotective effects of the vessel wall itself warrants intensive research. In particular, the endothelial glycocalyx, consisting of proteoglycans, glycoproteins and adsorbed plasma proteins, may play an essential role in protecting the vessel wall from atherosclerosis. RECENT DEVELOPMENTS: In this review, we will discuss the different vasculoprotective effects exerted by the endothelial glycocalyx, the factors that damage it, and the first preliminary data on the glycocalyx dimension in humans. Whereas most glycocalyx research has traditionally focused on the microvasculature, more recent data have underscored the importance of the glycocalyx in protecting the macrovasculature against pro-atherogenic insults. It has been shown that glycocalyx loss is accompanied by a wide array of unfavourable changes in both small and larger vessels. Pro-atherogenic stimuli increase the shedding of glycocalyx constituents into the circulation, contributing to the progressive loss of the vasculoprotective properties of the vessel wall. Novel techniques have facilitated reproducible measurements of systemic glycocalyx volume in humans. Consistent with experimental data, the volume of the human glycocalyx is also severely perturbed by exposure to atherogenic risk factors. SUMMARY: Cumulating evidence suggests that an intact glycocalyx protects the vessel wall, whereas disruption of the glycocalyx upon atherogenic stimuli increases vascular vulnerability for atherogenesis.     

Apoptosis Versus Cell Differentiation

Heat shock proteins HSP27, HSP70 and HSP90 are molecular chaperones whose expression is increased after many different types of stress. They have a protective function helping the cell to cope with lethal conditions. The cytoprotective function of HSPs is largely explained by their anti-apoptotic function. HSPs have been shown to interact with different key apoptotic proteins. As a result, HSPs can block essentially all apoptotic pathways, most of them involving the activation of cystein proteases called caspases. Apoptosis and differentiation are physiological processes that share many common features, for instance, chromatin condensation and the activation of caspases are frequently observed. It is, therefore, not surprising that many recent reports imply HSPs in the differentiation process. This review will comment on the role of HSP90, HSP70 and HSP27 in apoptosis and cell differentiation. HSPs may determine de fate of the cells by orchestrating the decision of apoptosis versus differentiation.     

Stem cells, vascular smooth muscle cells and atherosclerosis

Stem cells have the ability to differentiate into a variety of cells to replace dead cells or to repair tissue. Recently, accumulating evidence indicates that mechanical forces, cytokines and other factors can influence stem cell differentiation into vascular smooth muscle cells (SMCs). In developmental process, SMCs originate from several sources, which show a great heterogenicity in different vessel walls. In adult vessels, SMCs display a less proliferative nature, but are altered in response to risk factors for atherosclerosis. Traditional view on SMC origins in atherosclerotic lesions is challenged by the recent findings that stem cells and smooth muscle progenitors contribute to the development of atherosclerotic lesions. Vascular progenitor cells circulating in human blood and the presence of adventitia in animals are recent discoveries, but the source of these cells is still unknown. The present review gives an update on the progress of stem cell and SMC research in atherosclerosis, and discusses possible mechanisms of stem/progenitor cell differentiation that contribute to the disease process.     

胆固醇结晶激活动脉粥样硬化斑块巨噬细胞NLRP3炎症体的途径

动脉粥样硬化既是胆固醇在血管壁聚集的疾病,也是发生在动脉壁的一种低强度慢性炎症形式。近年来有研究证实胆固醇结晶在动脉粥样硬化发生发展中具有重要作用。新的显微技术证实,胆固醇结晶在动脉粥样硬化斑块形成的早期即已出现,并与早期炎症有关。胆固醇结晶通过诱发局部炎症,促进大的脂质核心形成;刺破纤维帽,导致斑块破裂进而促进动脉粥样硬化斑块的进展。在影响斑块进程中,NLRP3炎症体的激活对此发挥了重要的作用。NLRP3炎症体是研究最多最明确的炎症体,其与非炎症性疾病的发生发展密切相关。以胆固醇结晶激活NLRP3炎症体的途径作为研究靶点,为动脉粥样硬化的诊断和治疗提供了新的思路和方法。该文就胆固醇结晶在动脉粥样硬化斑块中激活巨噬细胞NLRP3炎症体的两种途径做一综述。     

Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms

Cardiovascular diseases are the human diseases with the highest death rate and atherosclerosis is one of the major underlying causes of cardiovascular diseases. Inflammatory and innate immune mechanisms, employing monocytes, innate receptors, innate cytokines, or chemokines are suggested to be involved in atherogenesis. Among the inflammatory pathways the cytokines are central players. Plasma levels of cytokines and related proteins, such as CRP, have been investigated in cardiovascular patients, tissue mRNA expression was analyzed and correlations to vascular diseases established. Consistent with these findings the generation of cytokine-deficient animals has provided direct evidence for a role of cytokines in atherosclerosis. In vitro cell culture experiments further support the suggestion that cytokines and other innate mechanisms contribute to atherogenesis. Among the initiation pathways of atherogenesis are innate mechanisms, such as toll-like-receptors (TLRs), including the endotoxin receptor TLR4. On the other hand, innate cytokines, such as IL-1 or TNF, or even autoimmune triggers may activate the cells. Cytokines potently activate multiple functions relevant to maintain or spoil homeostasis within the vessel wall. Vascular cells, not least smooth muscle cells, can actively contribute to the inflammatory cytokine-dependent network in the blood vessel wall by: (i) production of cytokines; (ii) response to these potent cell activators; and (iii) cytokine-mediated interaction with invading cells, such as monocytes, T-cells, or mast cells. Activation of these pathways results in accumulation of cells and increased LDL- and ECM-deposition which may serve as an 'immunovascular memory' resulting in an ever-growing response to subsequent invasions. Thus, vascular cells may potently contribute to the inflammatory pathways involved in development and acceleration of atherosclerosis.     

Amino acid analogs while inducing heat shock proteins sensitize CHO cells to thermal damage

Amino acid analogs have been shown to induce heat shock proteins (HSPs). We have examined the effect of these analogs on the thermal sensitivity of Chinese hamster fibroblasts (HA-1) and their stable heat-resistant variants. We found that exposure of HA-1 cells and their heat-resistant variants to canavanine or L-azetidine-2-carboxylic acid cause enhanced synthesis of the three major mammalian HSPs (molecular weight 70,000, 87,000, and 110,000 kd). Although the synthesis of HSPs was increased, the analogs did not induce thermotolerance, a transient ability to protect cells from thermal damage. On the contrary, the analog treatment increased the thermal sensitivity of HA-1 cells, but not of the heat-resistant strains, when these cells were exposed subsequently to elevated temperatures. Our tentative explanation for these findings is that the incorporation of amino acid analogs into HSPs or other cellular proteins sensitizes HA-1 cells to heat. The heat-resistant strains contain higher levels of constitutive HSPs. The additional functional HSPs in the heat-resistant variants may protect these cells from thermal stress. The presence of some newly synthesized analog-substituted, perhaps nonfunctional, HSPs need not affect this thermal protection.     

植物热激蛋白的功能及其基因表达的调控

本文介绍了植物热激蛋白的产：生、分布和分类。着重论述了热激反应的特点、植物热激蛋白的功能、热激基因表达与调控的研究进展。     

植物热激蛋白的功能及其基因表达的调控

本文介绍了植物热激蛋白的产生、分布和分类。着重论述了热激反应的特点、植物热激蛋白的功能、热激基因表达与调控的研究进展     

Cell-cell interactions mediate the response of vascular smooth muscle cells to substrate stiffness

The vessel wall experiences progressive stiffening with age and the development of cardiovascular disease, which alters the micromechanical environment experienced by resident vascular smooth muscle cells (VSMCs). In vitro studies have shown that VSMCs are sensitive to substrate stiffness, but the exact molecular mechanisms of their response to stiffness remains unknown. Studies have also shown that cell-cell interactions can affect mechanotransduction at the cell-substrate interface. Using flexible substrates, we show that the expression of proteins associated with cell-matrix adhesion and cytoskeletal tension is regulated by substrate stiffness, and that an increase in cell density selectively attenuates some of these effects. We also show that cell-cell interactions exert a strong effect on cell morphology in a substrate-stiffness dependent manner. Collectively, the data suggest that as VSMCs form cell-cell contacts, substrate stiffness becomes a less potent regulator of focal adhesion signaling. This study provides insight into the mechanisms by which VSMCs respond to the mechanical environment of the blood vessel wall, and point to cell-cell interactions as critical mediators of VSMC response to vascular injury.