单核细胞及其来源细胞在动脉粥样硬化炎症发病机制中的作用

心血管疾病尤其是冠状动脉粥样硬化心脏病,已经成为威胁人类健康的主要杀手。但是由于动脉粥样斑块形成的复杂性,动脉粥样硬化发生机制并不明确,该疾病发生的炎症学说成为研究热点。本文将对单核细胞及其来源的巨噬细胞和树突状细胞在动脉粥样硬化炎症发病机制中的作用做一综述,为寻找该疾病新的药物靶点提供思路。     

C反应蛋白与动脉粥样硬化

C反应蛋白（C-reactiveprotein,CRP）是人类非特异性急性期蛋白,是判断组织损伤和炎症反应的敏感指标之一。CRP的表达水平与动脉粥样硬化（atherosclerosis,AS）和心血管疾病的发生具有冠著的相关性。但是关于CRP是否是AS的独立危险因素并参与AS的发病机制,目前尚存在很大争议。新近的研究发现,CRP与某些特定的配体结合后,五聚体结构CRP可分离形成单体结构CRP。这一发现为研究CRP蛋白与AS的相互关系提供了新的线索,对CRP及其单体结构的深入研究,将有可能帮助人们找到治疗心血管疾病的有效方法。就炎性反应标志物CRP及其单体（monomeric CRP,mCRP）与动脉粥样硬化的相关研究进展进行综述,以探讨分析CRP在AS中的作用。     

Iron-load exacerbates the severity of atherosclerosis via inducing inflammation and enhancing the glycolysis in macrophages

Atherosclerosis is still the major cause of morbidity and mortality all over the world. Recently, it has been reported increased levels of tissue iron increase the risk of atherosclerosis. However, the detailed mechanism of iron-induced atherosclerosis progression is barely known. Here, we used apoE-deficient mice models to investigate the effects of low iron diet (<0 mg iron carbonyl/kg), high iron diet (25,000 mg iron carbonyl/kg) on atherosclerosis in vivo. As exhibited, we observed that CD68 was significant enriched by high iron diet in apoE-deficient mice. In addition, transforming growth factor β, tumor necrosis factor α, interleukin 6 (IL-6), IL-23, IL-10, and IL-1β levels were also greatly induced by high iron diet. Then, we found that the iron load promoted the inflammation response in macrophages. Moreover, macrophage polarization is a process by which macrophage can express various functional programs in activating macrophages. Here, we observed that iron-load macrophages were polarized toward a proinflammatory macrophage phenotype. The polarization of M1 macrophage was promoted by ferric ammonium citrate (FAC) in bone marrow derived macrophages (BMDMs). Furthermore, ECAR and cellular OCR in BMDM with or without FAC was examined. As shown, BMDM indicated with 50 μM FAC showed a significant increase in basic state and maximal ECAR in contrast to the control group. However, there was no significant difference in OCR. This indicated that the glycolysis was involved in the polarization of M1 macrophage triggered by iron-load. In conclusion, we indicated that the iron load exacerbates the progression of atherosclerosis via inducing inflammation and enhancing glycolysis in macrophages.     

On the modeling of snake venom serine proteinase interactions with benzamidine-based thrombin inhibitors

Pit viper venoms contain a number of serine proteinases that exhibit one or more thrombin-like activities on fibrinogen and platelets, this being the case for the kinin-releasing and fibrinogen-clotting KN-BJ from the venom of Bothrops jararaca. A three-dimensional structural model of the KN-BJ2 serine proteinase was built by homology modeling using the snake venom plasminogen activator TSV-PA as a major template and porcine kallikrein as additional structural support. A set of intrinsic buried waters was included in the model and its behavior under dynamic conditions was molecular dynamics simulated, revealing a most interesting similarity pattern to kallikrein. The benzamidine-based thrombin inhibitors alpha-NAPAP, 3-TAPAP, and 4-TAPAP were docked into the refined model, allowing for a more insightful functional characterization of the enzyme and a better understanding of the reported comparatively low affinity of KN-BJ2 toward those inhibitors.     

脂蛋白酯酶在动脉粥样硬化发生发展中的作用

脂蛋白酯酶(lipoprotein lipase, LPL)是调节甘油三酯代谢的关键酶,在动脉粥样硬化(atherosclerosis,As)的发生发展中起重要作用。LPL产生部位的差异决定了其具有促As作用还是抗As作用。其次,不同因素对LPL的调控也会使LPL对As产生相反的作用效果。本文综述了LPL在As发生发展中的作用机制以及不同因素对LPL的调控机制,对于As的防治具有重要意义。     

Role of Nrf2 in the pathogenesis of atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the vascular arterial walls. A number of studies have revealed the biological and genetic bases of atherosclerosis, and over 100 genes influence atherosclerosis development. Nrf2 plays an important role in oxidative stress response and drug metabolism, but the Nrf2 signaling pathway is closely associated with atherosclerosis development. During atherosclerosis progression, Nrf2 signaling modulates many physiological and pathophysiological processes, such as lipid homeostasis regulation, foam cell formation, macrophage polarization, redox regulation and inflammation. Interestingly, Nrf2 exhibits both pro- and anti-atherogenic effects in experimental animal models. These observations make the Nrf2 pathway a promising target to prevent atherosclerosis.     

Role of apoE in conformation-prone diseases and atherosclerosis

Three isoforms of human plasma apolipoprotein E (apoE) are ligands to lipoprotein receptors and influence in different manner the synthesis and catabolism of pro-atherogenic triglyceride-rich lipoproteins. Among three isoforms, the apoE4 isoform is associated with increased frequency of atherosclerosis and Alzheimer’s disease (AD). The conformational transitions of β-amyloid (Aβ) influenced by apoE and serum amyloid P (SAP) component are key events in AD development, the accumulation of intermediate diffusible and soluble oligomers of Aβ being of particular significance. SAP and apoE, in a different manner for the three isoforms, serve as “pathological” chaperones during the aggregation of Aβ considered as a conformation-prone process. In turn, apoE consisting of two domains self-associates in solution and intermediate structures differently populated for the three isoforms exist. The different structures of the three isoforms determine their different distribution among various plasma lipoproteins. The structural and metabolic consideration of the common apoE pathway(s) in two pathologies assumes four molecular targets for AD correction: (i) inhibition of the accumulation of diffusible soluble Aβ oligomers; (ii) inhibition of apoE synthesis and secretion by astrocytes, in particular, under lipid-lowering therapy; (iii) inhibition of the binding of apoE and/or SAP to Aβ; (iv) stimulation of the expression of cholesterol transporter ABCA1. Published in Russian in Biokhimiya, 2006, Vol. 71, No. 7, pp. 876–881.     

Role of pyroptosis in cardiovascular disease

Cardiac function is determined by the dynamic equilibrium of various cell types and the extracellular matrix that composes the heart. Cardiovascular diseases (CVDs), especially atherosclerosis and myocardial infarction, are often accompanied by cell death and acute/chronic inflammatory reactions. Caspase‐dependent pyroptosis is characterized by the activation of pathways leading to the activation of NOD‐like receptors, especially the NLRP3 inflammasome and its downstream effector inflammatory factors interleukin (IL)‐1β and IL‐18. Many studies in the past decade have investigated the role of pyroptosis in CVDs. The findings of these studies have led to the development of therapeutic approaches based on the regulation of pyroptosis, and some of these approaches are in clinical trials. This review summarizes the molecular mechanisms, regulation and cellular effects of pyroptosis briefly and then discusses the current pyroptosis studies in CVD research.     

Role of C5a-C5aR axis in the development of atherosclerosis

Complement component 5a (C5a) is a 74 amino acid glycoprotein and an important proinflammatory mediator that is cleaved enzymatically from its precursor, C5, on activation of the complement cascade. C5a is quickly metabolised by carboxypeptidases, forming the less-potent C5a desArg. C5a and C5a desArg interact with their receptors (C5aR and C5L2), which results in a number of effects which are essential to the immune response. C5a has a broad range of biological effects throughout the human body because the widespread expression of C5a receptors throughout the human organs enables C5a and C5a desArg to elicit a broad range of biological effects. Recently, accumulating evidence in humans and experimental animal models shows that the C5a-C5aR axis is involved in the development of atherosclerosis lesions. The absence or blockade of C5aRs greatly reduces the formation of atherosclerotic lesions or wire-injury-induced neointima formation in atherosclerosis-prone mice. Serum C5a level was related to the major adverse cardiovascular events in patients with advanced atherosclerosis and those with drug-eluting stent implantation. Thus, the C5a-C5aR axis may be a significant pathogenic driver of arteriosclerotic vascular disease, making C5a-C5aR inhibition an attractive therapeutic strategy.     

The role of monocytosis and neutrophilia in atherosclerosis

Monocytosis and neutrophilia are frequent events in atherosclerosis. These phenomena arise from the increased proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) and HSPC mobilization from the bone marrow to other immune organs and circulation. High cholesterol and inflammatory signals promote HSPC proliferation and preferential differentiation to the myeloid precursors (i.e., myelopoiesis) that than give rise to pro‐inflammatory immune cells. These cells accumulate in the plaques thereby enhancing vascular inflammation and contributing to further lesion progression. Studies in animal models of atherosclerosis showed that manipulation with HSPC proliferation and differentiation through the activation of LXR‐dependent mechanisms and restoration of cholesterol efflux may have a significant therapeutic potential.     

microRNA155在动脉粥样硬化发生过程中的网络调控机制

动脉粥样硬化(atherosclerosis,AS)是一种慢性进行性的血管炎症性疾病,其发病机制主要包括内皮细胞损伤,脂质浸润及炎症介质分泌等。microRNA155(miR-155)是参与AS炎性调控、免疫和自噬信号等通路的微小非编码RNA。系统性研究miR-155及其靶基因的网络调控机制,能全面理解miR-155在AS中的作用,促进其在临床诊断中的应用开发。利用miRNA靶基因预测数据库miRDB、miRmap和Starbase获取miR-155的靶基因集。R语言分析基因表达综合数据库(gene expression omnibus,GEO)共享平台动脉粥样硬化斑块差异表达基因(GSE24702),筛选出18 076个差异表达基因。利用基因集富集分析(gene set enrichment analysis,GSEA)分析,观察这些差异表达基因共同富集在IL6-JAK-STAT3信号通路、炎症反应和TNFα等炎症信号通路。与miR-155靶基因交叉匹配得到371个交集mRNA,其中159个在动脉粥样硬化斑块中上调,212个在动脉粥样硬化斑块中下调。基因本体(gene ontology,GO)及基因组数据库(kyoto encyclopedia of genes and genomes,KEGG)分析研究基因功能,GO富集分析371个差异基因主要富集炎症和凋亡信号通路的负调控等功能,KEGG分析371个差异基因主要富集TGFβ等炎症信号通路。蛋白相互作用网络(protein-protein interaction networks,PPI)分析获得关键节点基因是ARRB2、FBXO11、SOCS1、FBXO22、FBXO30、KRAS、RNF19A、TRIM32、HERC4、PJA1、RCHY1和DET1。本研究表明,miR-155主要通过调控炎症反应等相关信号通路影响斑块细胞炎症、自噬及凋亡等功能,进而影响动脉粥样硬化的各个进程。     

Trehalose administration attenuates atherosclerosis in rabbits fed a high-fat diet

Disruption of macrophage autophagy is a major contributor to macrophage dysfunction and subsequent inflammation leading to atherosclerosis. Trehalose is a natural disaccharide that is able to induce macrophage autophagy-lysosomal biogenesis and reduce inflammation. Here, we studied the efficacy of intravenous trehalose administration in reducing atherosclerotic plaque burden in high-cholesterol-fed rabbits. Adult male New Zealand white Rabbits were fed with a high-fat diet containing 1% cholesterol for 8 weeks followed by a cholesterol-free diet for the next 4 weeks. In the latter 4-week phase of the cholesterol-free diet, one group received intravenous trehalose solution at a dose of 350 mg/kg, three times per week. In the control group, an equivalent volume of PBS (3 mL) was administered with the same protocol. At the end of the 12th week of the study, all rabbits were anesthetized and aortic arch sections were collected followed by hematoxylin and eosin staining and assessment of plaque grading. Fasting serum lipids were also measured using routine enzymatic methods. At the end of the 12th week, there were no significant differences in the body weight and blood lipids between the control- and trehalose-treated groups. Intravenous trehalose administration significantly attenuated atherosclerotic plaque development as revealed by reduced plaque grading ( P = 0.048) and intima/media thickness ratio ( P = 0.017). Intimal thickening was also found to be reduced in the trehalose versus control group, though this reduction did not reach statistical significance. The present study provided evidence as to the efficacy of short-term intravenous trehalose administration in regressing atherosclerotic plaque in high-fat-fed rabbits.     

Role of the arterial smooth muscle cell in the pathogenesis of atherosclerosis

The development of an atherosclerotic lesion is characterised by a proliferation of arterial smooth muscle cells and an accumulation of cholesterol, cholesteryl esters and connective tissue. The main connective tissue components of an atherosclerotic lesion, i.e. acidic glycosaminoglycans and collagen, are synthesized by the smooth muscle cells. Cholesterol is chiefly derived from plasma lipoproteins, but there is an enhanced intracellular esterification of cholesterol in the cells of the lesions. The important role of the arterial smooth muscle cell in the development of atherosclerotic lesions has resulted in cultures of these cells being used as experimental models to study the pathogenesis of atherosclerosis. Such studies have revealed many blood-derived and other substances affecting proliferation, as well as lipid and connective tissue metabolism of arterial smooth muscle cells. In this way certain risk factors for cardiovascular disease have turned out to be associated with the metabolic disturbances of atherogenesis at the cellular level. Studies with cultured arterial smooth muscle cells have also demonstrated other factors for example one derived from aggregating platelets that may significantly contribute to the development of atherosclerotic lesions. On the other hand, certain inherent features of the smooth muscle cells of the lesions, such as enhanced proliferation and synthesis of glycosaminoglycans, may also contribute to the pathological changes.     

大鼠脑出血后大脑凝血酶受体-1长时效动态表达变化

目的:探讨脑出血(ICH)后凝血酶受体的动态及长时效表达。方法:将36只大鼠随机分为6组(n=6):正常组,ICH模型6h、24h、3d、7d和14d组。Ⅶ-S型胶原酶诱导大鼠ICH模型。免疫组化方法测定不同时间点大鼠ICH后血肿周围水肿组织PAR-1蛋白的表达;RT-PCR方法检测蛋白酶激活的受体(PAR)-1mRNA的表达。结果:正常组大鼠大脑PAR-1蛋白和PAR-1mRNA表达轻度阳性,模型组6h时PAR-1表达强度开始增强,24hPAR-1表达进一步增强,于3d达到高峰,然后开始下降,7d时明显下降,14d进一步下降,但仍未至正常组水平。模型组各时间点PAR-1阳性细胞数、PAR-1mRNA吸光度比值升高与正常组比较均有显著性差异(P<0.05或P<0.01)。此外,PAR-1蛋白在脑微血管内皮细胞在体有明显的表达。结论:脑微血管内皮细胞存在PAR-1,ICH后凝血酶激活PAR-1不仅是ICH后脑水肿产生的始动因素,而且参与了脑水肿的发展过程。     

Pharmacological basis of different targets for the treatment of atherosclerosis

The development of atherosclerotic plaque is a highly regulated and complex process which occurs as a result of structural and functional alterations in endothelial cells, smooth muscle cells (SMCs), monocytes/macrophages, T-lymphocytes and platelets. The plaque formation in the coronary arteries or rupture of the plaque in the peripheral vasculature in latter stages of atherosclerosis triggers the onset of acute ischemic events involving myocardium. Although lipid lowering with statins has been established as an important therapy for the treatment of atherosclerosis, partially beneficial effects of statins beyond decreasing lipid levels has shifted the focus to develop newer drugs that can affect directly the process of atherosclerosis. Blockade of renin angiotensin system, augmentation of nitric oxide availability, reduction of Ca(2+) influx, prevention of oxidative stress as well as attenuation of inflammation, platelet activation and SMC proliferation have been recognized as targets for drug treatment to control the development, progression and management of atherosclerosis. A major challenge for future drug development is to formulate a combination therapy affecting different targets to improve the treatment of atherosclerosis.     

Role of vascular smooth muscle cell in the inflammation of atherosclerosis

Atherosclerosis is a pathologic process occurring within the artery, in which many cell types, including T cell, macrophages, endothelial cells, and smooth muscle cells, interact, and cause chronic inflammation, in response to various inner- or outer-cellular stimuli. Atherosclerosis is characterized by a complex interaction of inflammation, lipid deposition, vascular smooth muscle cell proliferation, endothelial dysfunction, and extracellular matrix remodeling, which will result in the formation of an intimal plaque. Although the regulation and function of vascular smooth muscle cells are important in the progression of atherosclerosis, the roles of smooth muscle cells in regulating vascular inflammation are rarely focused upon, compared to those of endothelial cells or inflammatory cells. Therefore, in this review, we will discuss here how smooth muscle cells contribute or regulate the inflammatory reaction in the progression of atherosclerosis, especially in the context of the activation of various membrane receptors, and how they may regulate vascular inflammation. [BMB Reports 2014; 47(1): 1-7]