早期动脉粥样硬化血管内皮细胞损伤机制研究进展

自Ross提出动脉粥样硬化（AS）发病机制的＂损伤反应假说＂以来,血管内皮细胞损伤在AS的形成与发展中的地位日趋受到关注。糖尿病、高血脂和高血压等多种疾病,氧化应激以及炎症反应等各种相关因子作用于内皮细胞后,致其内皮细胞的调节血管张力、抗凝与促凝等功能障碍,血管活性物质、细胞因子、     

NF-κB在动脉粥样硬化中的始动作用

动脉粥样硬化是一种具有慢性炎症反应的病理过程 ,血管内皮细胞在引发和扩大炎症反应中起了重要作用 ,以NF κB家族为调控中心的内皮细胞活化及炎症诱导有可能成为动脉粥样硬化形成的共同途径 ,选择性保护内皮细胞 ,可能为治疗动脉粥样硬化提供新的途径。     

NF—KB在动脉粥样硬化中的始动作用

动脉粥样硬化是一种具有慢性炎症反应的病理过程．血管内皮细胞在引发和扩大炎症反应中起了重要作用．以NF—kB家族为调控中心的内皮细胞活化及炎症诱导有可能成为动脉粥样硬化形成的共同途径，选择性保护内皮细胞．可能为治疗动脉粥样硬化提供新的途径。     

炎症相关细胞在动脉粥样硬化发生发展过程中的作用

炎症反应为动脉粥样硬化(AS)发生发展过程中的核心因素。与炎症相关的细胞,如血管内皮细胞、单核/巨噬细胞、T淋巴细胞和血管平滑肌细胞,及其分泌的细胞因子与AS的发生、发展密切相关。因此,认识AS病理过程中炎症细胞间的相互作用机制并加以干预,是目前防治AS研究的一个重要方向。     

血管细胞黏附分子-1与动脉粥样硬化机制的研究现状北大核心CSCD

动脉粥样硬化(AS)是一种慢性的、以脂质发育为特征的炎症过程。血管细胞黏附分子-1(VCAM-1)是一种炎症因子,表达在炎症环境下的内皮细胞膜上,介导白细胞的滚动和黏附。在AS开始初期,免疫细胞和脂质浸润血管壁形成斑块,VCAM-1在这个过程中发挥了重要的作用。本文对目前AS发生、发展过程中VCAM-1高表达的诱因及其病理机制,以及通过减少VCAM-1表达抗AS的药物进行了综述。     

MCP-1、VEGF与动脉粥样硬化的关系

动脉粥样硬化(arteriosclerosis AS)是慢性炎症性疾病,主要由于血管内皮损伤、继发炎症、免疫功能障碍三者相互作用形成。血管壁慢性炎症是AS的特征,动脉硬化灶中炎性细胞主要为单核/巨噬细胞。已知单核细胞趋化蛋白-1(monocyte chermtach protein-1 MCP-1)是单核/巨噬细胞特异的趋化性因子,其主要功能是趋化和激活单核/巨噬细胞至炎症部位,参与炎症反应、调节免疫,并促进动脉粥样硬化的形成;血管内皮生长因子(Endogenous vascular endothelial growth factor VEGF)是特异血管内皮细胞促有丝分裂原,在血管内皮生成细胞增殖有关的病理过程中占首要地位,最近报道它在AS中起重要作用。     

脂蛋白相关磷脂酶A2与动脉粥样硬化疾病

<正>心血管疾病位列全球死因第1位,冠心病(CHD)约占其中的49%,动脉粥样硬化(AS)是心脑血管疾病的重要病理基础,因此,探讨AS的发病机制及防治措施是心血管领域的研究热点之一。自从1995年,Ross[1]提出AS是一种炎症疾病,是动脉壁内皮细胞及平滑肌细胞受到损伤后的一种炎性纤维组织增生性的反应后,近年来,随着对动脉粥样硬化研究     

中药复方抗动脉粥样硬化作用机制的研究进展

心血管疾病在全球的发病率和致死率仍居高不下,动脉粥样硬化(AS)是心血管疾病的重要病理基础,其致病机制至今尚未完全明确.目前主要认为,AS与血管内皮细胞损伤、脂质代谢紊乱、炎症反应、自噬和凋亡失衡等因素有关.传统中草药特别是中药复方在防治AS中取得良好疗效,对中药复方抗AS的药效及作用机制研究也越来越多.通过检索近5年...     

药物治疗动脉粥样硬化新途径——抗炎作用

越来越多的实验证据和临床资料表明 ,炎症反应贯穿了动脉粥样硬化发生和发展的整个过程。炎症可以激活单核细胞和刺激内皮细胞产生促炎因子 ,进而刺激血管平滑肌细胞迁移、增殖 ,炎症继续发展 ,细胞释放的水解酶、细胞因子等进一步加重损伤 ,最终形成斑块。因此 ,根据这一新的发病机制 ,通过抗炎途径治疗动脉粥样硬化已引起人们的极大关注。该文对药物通过调节C反应蛋白、CD4 0 CD4 0L、感染和NF κB抗动脉粥样硬化的研究进展作一综述     

动脉粥样硬化的免疫调节与疫苗研制

动脉粥样硬化(atherosclerosis,AS)活化免疫系统产生的免疫应答,既可能导致持久性的动脉炎症反应而促进AS,也可能抑制动脉炎症反应和AS。通过免疫调节,选择性抑制促AS的免疫应答或促进抗AS的免疫应答,可能对AS产生防治作用。     

Sandwich ELISA法测定NF-κB

目的　建立一种操作简便、安全的核因子 κB(NF κB)活性检测方法。方法　采用夹心酶联免疫吸附测试法(SandwichELISA) ,酶标仪 ,验证NF κB活化的抑制剂反义白介素 1受体相关激酶 2 (IRAK 2 )寡核苷酸和N α Tosyl L lysinechloromethylketone(TLCK)对NF κB活性的抑制作用。结果　SandwichELISA测定结果表明 ,与对照组相比 ,用不同浓度反义IRAK 2寡核苷酸 (1,2 ,3,4μg )或TLCK(1,10 ,10 0 μmol·L-1)处理细胞后 ,NF κB活化受到不同程度的抑制 ,表现为吸光度值下降的幅度不同。结论　Sand wichELISA法可用于NF κB活性检测。     

Crucial role of Toll-like receptors in the zinc/nickel-induced inflammatory response in vascular endothelial cells

Our previous studies indicated that zinc induced inflammatory response in both vascular endothelial cells and promonocytes. Here, we asked if other metals could cause the similar effect on vascular endothelial cells and tried to determine its underlying mechanism. Following screening of fifteen metals, zinc and nickel were identified with a marked proinflammatory effect, as determined by ICAM-1 and IL-8 induction, on human umbilical vein endothelial cells (HUVECs). Inhibiting protein expression of myeloid differentiation primary response protein-88 (MyD88), a Toll-like receptor (TLR) adaptor acting as a TLR-signaling transducer, significantly attenuated the zinc/nickel-induced inflammatory response, suggesting the critical roles of TLRs in the inflammatory response. Blockage of TLR-4 signaling by CLI-095, a TLR-4 inhibitor, completely inhibited the nickel-induced ICAM-1 and IL-8 expression and NFκB activation. The same CLI-095 treatment significantly blocked the zinc-induced IL-8 expression, however with no significant effect on the ICAM-1 expression and a minor inhibitory effect on the NFκB activation. The finding demonstrated the differential role of TLR-4 in regulation of the zinc/nickel-induced inflammatory response, where TLR-4 played a dominant role in NFκB activation by nickel, but not by zinc. Moreover, inhibition of NFκB by adenovirus-mediated IκBα expression and Bay 11-7025, an inhibitor of cytokine-induced IκB-α phosphorylation, significantly attenuated the zinc/nickel-induced inflammatory responses, indicating the critical of NFκB in the process. The study demonstrates the crucial role of TLRs in the zinc/nickel-induced inflammatory response in vascular endothelial cells and herein deciphers a potential important difference in NFκB activation via TLRs. The study provides a molecular basis for linkage between zinc/nickel exposure and pathogenesis of the metal-related inflammatory vascular disease.     

反义磷脂酰肌醇3-激酶寡脱氧核苷酸抑制白介素-1诱导的NF-κB活化

目的　研究反义磷脂酰肌醇 3 激酶 (PI 3 激酶 )寡脱氧核苷酸 (oligodeoxynucleotides,ODN)对核因子 κB(NF κB)活化的影响。方法　Lipofectin介导反义PI 3 激酶ODN转染HepG2细胞 ,以逆转录PCR法检测PI 3 激酶mRNA表达水平 ,用SandwichELISA法检测NF κB的活化。结果　(1)反义PI 3 激酶ODN抑制PI 3 激酶mRNA表达。 (2 )反义PI 3 激酶ODN呈剂量 (1～ 8μg)和时间 (5～ 2 4h)依赖性地抑制NF κB活化 ,2 μg反义PI 3 激酶ODN与细胞共孵育 8h时抑制效果最好。结论　反义PI 3 激酶ODN通过阻断PI 3 激酶表达抑制NF κB活化 ,预示反义PI 3 激酶ODN可潜在抑制IL 1的炎症活性     

白介素-1受体相关激酶-2反义寡核苷酸对白介素-1和肿瘤坏死因子激活核因子-κB的不同影响

目的　研究白介素 1受体相关激酶 2 (IRAK 2 )在白介素 1(IL 1)与肿瘤坏死因子 (TNF)激活核因子 κB(NF κB)过程中的作用。方法　IRAK 2反义寡核苷酸转染人胚肾细胞 (2 93细胞 ) ,阻断IRAK 2的表达 ,用IL 1及肿瘤坏死因子刺激细胞后 ,用夹心ELISA方法检测NF κB活性。结果　以IRAK 2反义寡核苷酸预处理可明显减弱IL 1诱导的NF κB活性 ,此效应强度存在时间和浓度依赖性 ,但I RAK 2反义寡核苷酸对肿瘤坏死因子诱导的NF κB活性无影响。结论　IRAK 2反义寡核苷酸对IL 1和TNF激活NF κB有不同影响。IRAK 2在IL 1诱导的NF κB信号转导通路中起关键作用     

三七总皂苷对心肌缺血再灌注中中性粒细胞核因子-κB活化及其粘附的影响

目的　研究三七总皂苷对心肌缺血 -再灌注时中性粒细胞 (PMN)内核因子 κB(NF κB)活性变化、细胞间粘附分子 (ICAM 1)表达及中性粒细胞粘附的影响。方法　新西兰兔 2 4只分为①缺血 -再灌注组 (I R) :结扎兔左冠状动脉前降支造成心肌缺血 4 5min后再开放 ;②三七总皂苷 (PNS)预处理组 (IR +PNS) :在心肌缺血前 10min静脉注射PNS(10 0mg·kg-1) ;③假手术对照组 (Sham) ;每组又分缺血前(0 )、再灌注后 30、6 0、90、12 0、2 4 0、36 0min时相点。用流式细胞仪检测中性粒细胞ICAM 1的表达 ,凝胶电泳迁移率分析检测NF κB的活性 ,测定中性粒细胞与脐静脉内皮细胞(EC 340 )的粘附率。结果　在缺血 -再灌注组中心肌再灌注 30min后NF κB活性开始增高 ,12 0min达到高峰 ,之后活性下降 ;中性粒细胞ICAM 1的表达在心肌再灌注 12 0min开始增高 ,并与并与中性粒细胞粘附率升高有相关性 ;在三七总皂苷预处理组 ,PNS能抑制NF κB的活化及中性粒细胞ICAM 1的表达和中性粒细胞粘附。结论　心肌缺血 -再灌注时刺激NF κB的活化 ,启动中性粒细胞ICAM 1的表达而参与缺血 -再灌注损伤的发生过程 ;三七总皂苷能抑制中性粒细胞内核因子 κB的活化 ,减少细胞间粘附分子表达及中性粒细胞粘附而起到心肌保护的作用     

双氢青蒿素对BXSB小鼠狼疮肾炎的作用及机制研究

目的　观察双氢青蒿素 (Dihydroqinghaosu ,DQHS)对BXSB小鼠狼疮肾炎 (LN)病理改变的影响及对其肾组织核蛋白提取物中核转录因子 κB(NF κB)活化和NF κBp6 5蛋白表达的影响 ,探讨DQHS治疗系统性红斑狼疮 (systemiclupuserythematosus,SLE)的分子机制。 方法　对低温冰冻肾组织进行免疫荧光检测 ;用Westernblot的方法检测肾组织核蛋白提取物中NF κBp6 5蛋白的表达 ;以凝胶电泳迁移率改变试验 (Electrophreticmobilityshiftassay ,EMSA)对NF κB的活化进行检测。结果　免疫荧光检测显示 :模型对照组及DQHS(5mg·kg-1)剂量组小鼠肾脏组织中多种免疫球蛋白 (IgG ,IgA ,IgM)和补体 (C3 ,C1q)的荧光检测呈强阳性 ,DQHS高剂量 (12 5mg·kg-1)和中剂量 (2 5mg·kg-1)组除IgG和补体C3 呈微弱阳性外 ,IgA ,IgM和补体C1q均为阴性 ;与正常组相比较 ,BXSB小鼠肾组织核蛋白提取物中NF κB的活化及其p6 5蛋白的表达均增加 ,其中 p6 5蛋白表达的增加差异具有显著性 (P <0 0 1) ;与模型组相比较 ,DQHS3个剂量 (12 5、2 5、5mg·kg-1)组BXSB小鼠肾组织核蛋白提取物中NF κB的活化及其p6 5蛋白的表达均有不同程度的降低 ,其中 p6 5蛋白表达的降低差异具有显著性 (P <0 0 1)。结论　DQHS能抑制肾组织中NF κB的活化及其     

雷公藤对豚鼠哮喘模型核因子-κB表达的作用

目的　探讨雷公藤对核因子 κB(NF κB)在豚鼠哮喘模型中表达的影响。方法　豚鼠用 10 %卵白蛋白 (OA)溶液1ml腹腔注射致敏 ,2wk后用 1%OA溶液超声雾化吸入致其哮喘发作 ,每日 1次 ,共 1wk ;测定肺功能并观察气道壁嗜酸性粒细胞 (EOS)浸润情况 ;用免疫组织化学染色方法观察NF κB在豚鼠肺组织中的表达变化。结果　NF κB主要表达在气道壁内的细胞 ,对照组、模型组、雷公藤内酯醇 ( 10 0mg·kg-1ip)组的胞核阳性的细胞数占气道上皮细胞数百分比分别为 14 3 %± 2 6%、3 2 5 %± 5 8%和 19 7%±2 1%。结论　雷公藤内酯醇能显著抑制哮喘豚鼠气道壁内细胞NF κB的表达 ,可能是雷公藤治疗哮喘的作用机制之一。     

Galectin‐3 aggravates ox‐LDL‐induced endothelial dysfunction through LOX‐1 mediated signaling pathway

Galectin‐3, a biomarker linking oxidative stress and inflammation, participates in different mechanisms related to atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. Accumulating evidence indicates that galectin‐3 may also promote atherogenesis through inducing endothelial dysfunction. Lectin‐like oxidized low‐density lipoprotein (oxLDL) receptor‐1 (LOX‐1), a receptor for oxLDL uptake, contributes to oxLDL‐induced endothelial dysfunction. Whether galectin‐3 induces endothelial dysfunction through modulation of LOX‐1‐mediated signaling remains unclear. In the present study, we explored the mechanisms underlying galectin‐3 enhanced cytotoxicity of oxLDL in human umbilical vein endothelial cells (HUVECs) and the role of LOX‐1. Incubation of HUVECs with galectin‐3 increased the expression of LOX‐1 in RNA and protein levels. In addition, the expression of LOX‐1 induced by oxLDL was promoted by galectin‐3. However, pretreatment of LOX‐1 antibody reduced LOX‐1 mRNA expression level in cells with oxLDL plus galectin‐3 incubation. Compared to cells treated with oxLDL alone, reactive oxygen species (ROS) generation via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and subsequent activation of p38 mitogen‐activated protein kinases followed by nuclear factor kappa B (NF‐κB) activation and related inflammatory responses including adhesion molecule expression, adhesiveness of monocytic cells, and IL‐8 release were also aggravated in cells treated with galectin‐3 combined with oxLDL. Compared to cells treated with galectin‐3 plus oxLDL group. We found that LOX‐1 antibody mitigated NADPH oxidase activity, p‐38 up‐regulation, NF‐κB activation, and proinflammatory responses in cells treated with galectin‐3 combined with oxLDL. We conclude that galectin‐3 enhances endothelial LOX‐1 expression and propose a new mechanism by which galectin‐3 may promote endothelial dysfunction by inducing inflammation via LOX‐1/ROS/p38/NF‐κB‐mediated signaling pathway.     

Peoniflorin prevents the adhesion between inflammatory endothelial cells and leukocytes through inhibiting the activation of MAPKs and NF‐κB

The vascular endothelium can be activated by multiple factors, including lipopolysaccharide (LPS) functioning as a key component of the inflammatory response. Activated endothelium promotes the recruitment of leukocytes mainly by releasing various adhesion molecules and amplifies inflammation via a feedback loop. Peoniflorin, the main active constituent of the roots of Paeonia lactiora Pall., possesses anti‐inammatory, anti‐infective, and anti‐platelet aggregative properties. To elucidate the anti‐inammatory mechanism of peoniflorin, the present study was conducted to address its effects on the adhesion of inflammatory endothelial cells to leukocytes. Peoniflorin substantially reduced adhesion of either human acute monocytic leukemia cells (THP‐1) or human acute promyelocytic leukemia cells (HL‐60) to LPS‐stimulated human umbilical vein endothelial cells (HUVECs). It also markedly down‐regulated the expression of E‐selectin at both the gene and protein levels. However, peoniflorin only slightly reduced expression of intercellular adhesion molecule‐1 (ICAM‐1). Signal pathway analysis indicated that peoniflorin reduced phosphorylation of c‐Jun NH₂‐terminal kinase (JNK) and p38 kinase, as well as the phosphorylation and degradation of IκB‐α in HUVECs. These findings suggest that prevention of the adhesion between inflammatory endothelial cells and leukocytes contributes, at least partially, to the anti‐inflammation action of peoniflorin. The anti‐adhesion mechanisms of peoniflorin were involved in the down‐regulation of the activation of mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB), and a reduction of adhesion molecule expressions in endothelial cells. Drug Dev Res 2010.© 2010 Wiley‐Liss, Inc.