辛伐他汀对兔髂动脉粥样硬化斑块中组织因子表达及活性的作用

目的观察辛伐他汀对兔动脉粥样硬化斑块内组织因子(TF)表达和活性的影响.方法20只雄性新西兰大白兔,采用高胆固醇喂养和动脉内膜剥脱术制作兔髂动脉粥样硬化模型,随机分为两组①不接受治疗(对照组);②辛伐他汀治疗(辛伐他汀治疗组,每日10 mg/kg体重).免疫组化和双染免疫组化的方法观察TF在斑块中的分布;酶联免疫吸附(ELISA)法测定TF抗原含量;底物发色法测定斑块TF活性.结果兔动脉粥样硬化斑块中所有细胞类型均有TF的表达,其中巨噬细胞是TF的主要来源.辛伐他汀治疗可减少斑块内巨噬细胞的数量,还可增加成熟型平滑肌细胞的数量,同时明显减少斑块内TF的表达及活性(P＜0.01).结论减少动脉粥样硬化斑块内TF的表达及活性是辛伐他汀减少动脉粥样硬化血栓性并发症的一个重要机制.     

动脉粥样硬化与组织因子

组织因子在动脉粥样硬化过程中发挥重要作用,内皮细胞、单核/巨噬细胞、细胞的趋化和迁移均与之密切相关,动脉粥样硬化和再狭窄过程中的平滑肌细胞增殖也与之相关。     

组织因子途径抑制物在不稳定斑块发生的作用

动脉粥样硬化最严重的后果之一是血栓形成。已知组织因子是血栓形成的起始因子,组织因子途径抑制物-1是组织因子的生理抑制剂,组织因子途径抑制物-2能抑制细胞外基质降解。通过分子改造,研制出重组人源性长效组织因子途径抑制物(rhlTFPI),其不仅能对抗动脉粥样硬化并发的血栓形成,而且能抑制内膜的增生。探讨rhlTFPI与斑块的稳定性及组织因子途径抑制物-2与细胞外基质降解关系,具有重要的理论意义;有助于今后应用rhlTFPI和重组组织因子途径抑制物-2维持斑块稳定、防治动脉粥样硬化疾病。     

人动脉粥样硬化病变中组织因子和白细胞介素18的表达

目的探讨炎症与凝血机制在动脉粥样硬化发病机制中的相互作用。方法用HE染色方法观察人动脉粥样硬化病理变化,用免疫组织化学法研究人动脉粥样硬化病变中凝血因子组织因子和促炎细胞因子白细胞介素18的表达。结果2例正常动脉的内皮细胞未见组织因子抗原表达,组织因子在Ⅰ型病变(n=6)的内皮细胞中有3例表达,Ⅱ型病变(n=8)的内皮细胞中有5例表达,Ⅲ～Ⅵ型病变的内皮细胞中几乎都表达;各期病变中的巨噬细胞和平滑肌细胞均表达组织因子;有白细胞介素18表达的标本共14例(14/40,占35%),白细胞介素18阳性表达的病变中组织因子也有表达。结论动脉粥样硬化病变与组织因子、白细胞介素18表达密切相关。     

组织因子在血栓形成中的作用

组织因子（ＴＦ）是一种跨膜糖蛋白,为凝血因子Ⅶａ在细胞表面的受体和辅因子,晃凝血过程的启动因子。生理情况下,与血液直接接触的细胞并不表达ＴＦ。最近的研究表明,ＴＦ的活动与动脉继样硬化所致的血栓形成有密切关系。文章重点探讨ＴＦ在动脉粥样硬化、血栓形成和溶栓后血栓性再闭塞中的作用及其研究进展。     

大黄素稳定小鼠动脉粥样硬化斑块的机制

目的 探讨大黄素对小鼠动脉粥样硬化(AS)斑块内基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶-9(MMP-9)及金属蛋白酶组织抑制剂-1(TIMP-1)的影响,及其稳定AS斑块的机制.方法 30只7周龄ApoE-/-小鼠,适应性喂养1 w后,随机分为空白对照组、模型组和大黄素组,每组10只.空白对照组给予普通饮食,模型组给予高脂饮食,大黄素组在高脂饮食基础上给予大黄素60 mg·kg-1·d-1灌胃,空白对照组和模型组给予等量生理盐水灌胃.实验20 w末处死全部小鼠,留取主动脉根部标本,用免疫组织化学方法检测AS斑块内MMP-2、MMP-9及TIMP-1表达情况.结果 大黄素组MMP-2、MMP-9的表达较模型组显著减少(P<0.01、P<0.05),TIMP-1表达显著增高(P<0.01).结论 大黄素可通过减少斑块处MMP-2、MMP-9的表达,增高TIMP-1表达,起到稳定AS斑块的作用.     

动脉粥样硬化不稳定斑块相关因子的研究进展

据我国2018年心血管病报告[1]统计,我国心血管病患病率及死亡率处于上升阶段,心血管病死亡率居首位,高于肿瘤及其他疾病,占居民疾病死亡构成的40％以上.动脉粥样硬化(AS)不稳定斑块的破裂或糜烂导致冠状动脉(冠脉)内血栓形成,被认为是大多数急性冠脉综合征(ACS)发病的主要病理基础.     

组织因子及组织因子途径抑制物与动脉粥样硬化的关系

组织因子及组织因子途径抑制物可促发、调节粥样血栓形成过程。组织因子是血栓形成的启动因子,具有促进血管新生和细胞迁移的功能,通过凝血功能及非凝血功能在动脉粥样硬化斑块中起作用,而组织因子途径抑制物是组织因子途径生理性抑制剂。文章探讨组织因子及组织因子途径抑制物在动脉粥样硬化斑块中的作用,对临床治疗因动脉粥样硬化引起的心血管疾病具有重要的理论和现实意义。     

组织因子在血栓形成中的作用

组织因子（ Ｔ Ｆ） 是一种跨膜糖蛋白，为凝血因子Ⅶａ 在细胞表面的受体和辅因子，是凝血过程的启动因子。生理情况下，与血液直接接触的细胞并不表达 Ｔ Ｆ。最近的研究表明， Ｔ Ｆ 的活动与动脉粥样硬化所致的血栓形成有密切关系。文章重点探讨 Ｔ Ｆ 在动脉粥样硬化、血栓形成和溶栓后血栓性再闭塞中的作用及其研究进展。     

异常剪切应力上调组织蛋白酶L在动脉粥样硬化斑块中表达

目的观察组织蛋白酶L(Cathepsin L)在异常剪切切应力诱导的动脉粥样硬化斑块中的表达,探讨Cathepsin L在动脉粥样硬化病变中的作用。方法采用套环法建立兔颈总动脉局部狭窄的动物模型,喂养4周;数值模拟法模拟局部狭窄远心端和近心端流场特性以及剪切应力分布;酶法测定血浆中总胆固醇、甘油三酯以及HDL水平;HE染色观察病理学改变;油红O染色观察病变处脂质的蓄积;免疫组织化学法检测Cathepsin L的表达。结果 4周后,兔血脂水平没有明显改变。套环形成局部狭窄后,颈总动脉血流流场发生显著的扰动,狭窄远心端有涡流以及二次流形成;狭窄近心端形成局部高剪切应力区域,而在远心端形成振荡的低剪切应力区域(0～0.3 Pa)。HE染色显示颈总动脉狭窄的近心端和远心端均有明显的内膜增生以及动脉粥样硬化斑块形成,近心端比远心端病变更严重。油红O染色显示有大量的脂质沉积;免疫组织化学染色结果表明病变中有大量的Cathepsin L表达,主要分布于斑块中的巨噬细胞和平滑肌细胞,并且近心端Cathepsin L的表达量明显高于远心端量,而对照侧血管仅有微量的Cathepsin L表达。结论切应力特性调节Cathepsin...     

Cocaine unbalances endothelial tissue factor and tissue factor pathway inhibitor expression

Cocaine consumption can lead to myocardial infarction. Tissue factor (TF) has been implicated in acute coronary syndromes, and the balance of TF and tissue factor pathway inhibitor (TFPI) determines initiation of thrombus formation. This study was designed to investigate the effect of cocaine on endothelial TF and TFPI expression. Cocaine (10(-8)-10(-5) mol/l) increased thrombin-induced TF expression by 24% at 10(-7) mol/l (P < 0.001) without affecting basal TF expression. In contrast, cocaine reduced endothelial TFPI expression by 47% at 10(-7) mol/l (P < 0.01). Moreover, thrombin impaired endothelial TFPI expression, and cocaine (10(-8) mol/l) further reduced TFPI expression by 33% as compared to thrombin (P < 0.02). These effects occur at cocaine concentrations usually present in plasma of consumers. Given the importance of TF in the pathogenesis of acute coronary syndromes, TF induction in conjunction with TFPI suppression may be relevant for the increased frequency of myocardial infarction observed in cocaine consumers.     

Timing of estrogen replacement influences atherosclerosis progression and plaque leukocyte populations in ApoE-/- mice

Studies of the effects of estrogen replacement therapy on coronary heart disease risk have produced conflicting results. We hypothesize that this may be explained by differences in the length of estrogen deficiency prior to initiation of treatment and associated variation in plaque inflammation or stage of progression. The goal of this study was to determine whether estrogen administered after a period of deficiency affects plaque progression and leukocyte populations. Ovariectomized ApoE-/- mice were treated as follows: group 1: continuous estrogen for 90 days (E+/+); group 2: placebo for 45 days followed by estrogen for 45 days (E-/+); group 3: estrogen for 45 days followed by placebo for 45 days (E+/-); and group 4: placebo for 90 days (E-/-). Serum lipoprotein concentrations, plaque size and inflammatory cell (macrophage, CD3+, CD4+, CD8+, dendritic cell, and NK cell) densities were quantified. Plaque size was smaller in groups receiving early estrogen therapy. CD3+ and total inflammatory cell densities were lower in late estrogen therapy groups. The CD8 to dendritic cell ratio was significantly lower in the E-/+ group only. These results suggest that a period of estrogen deficiency followed by reintroduction alters the immunologic environment of atherosclerotic lesions as well as plaque progression.     

丹参多酚酸盐对ApoE基因敲除小鼠血清脂质的干预作用

目的:观察中药丹参多酚酸盐对高脂饮食ApoE-/-小鼠脂质代谢的影响,探讨丹参多酚酸盐抗动脉粥样硬化作用机制。方法:将4周龄雄性C57BL/6J ApoE-/-小鼠喂食高脂饮食,随机分为4组。模型组腹腔注射生理盐水、丹参多酚酸盐干预分为低剂量组(60 mg/kg)、中剂量组(120 mg/kg)和高剂量组(240 mg/kg)腹腔注射丹参多酚酸,另设C57BL/6J野生型小鼠为对照组。于24周末时处死各组小鼠,留取血清,检测各组小鼠血清总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)水平。结果:与对照组比较,ApoE-/-鼠血清TC、LDL-C均明显升高(P<0.05),表明敲除ApoE基因能导致血脂代谢紊乱。应用丹参多酚酸盐后,各干预组TC、LDL-C水平均明显降低(P<0.05),但TG和HDL-C水平无明显改变,中、高剂量组尤为显著。结论:丹参多酚酸盐可降低ApoE-/-小鼠血清TC和LDL-C水平,可能是其抗动脉粥样硬化的作用机制之一。     

Thrombospondin-1 deficiency accelerates atherosclerotic plaque maturation in ApoE-/- mice

Thrombospondin (TSP)1 is implicated in various inflammatory processes, but its role in atherosclerotic plaque formation and progression is unclear. Therefore, the development of atherosclerosis was compared in ApoE(-/-) and Tsp1(-/-)ApoE(-/-) mice kept on a normocholesterolemic diet. At 6 months, morphometric analysis of the aortic root of both mouse genotypes showed comparable lesion areas. Even when plaque burden increased approximately 5-fold in ApoE(-/-) and 10-fold in Tsp1(-/-)ApoE(-/-) mice, during the subsequent 3 months, total plaque areas were comparable at 9 months. In contrast, plaque composition differed substantially between genotypes: smooth muscle cell areas, mostly located in the fibrous cap of ApoE(-/-) plaques, both at 6 and 9 months, were 3-fold smaller in Tsp1(-/-)ApoE(-/-) plaques, which, in addition, were also more fibrotic. Moreover, inflammation by macrophages was twice as high in Tsp1(-/-)ApoE(-/-) plaques. This correlated with a 30-fold elevated incidence of elastic lamina degradation, with matrix metalloproteinase-9 accumulation, underneath plaques and manifestation of ectasia, exclusively in Tsp1(-/-)ApoE(-/-) mice. At 9 months, the necrotic core was 1.4-fold larger and 4-fold higher numbers of undigested disintegrated apoptotic cells were found in Tsp1(-/-)ApoE(-/-) plaques. Phagocytosis of platelets by cultured Tsp1(-/-) macrophages revealed the instrumental role of TSP1 in phagocytosis, corroborating the defective intraplaque phagocytosis of apoptotic cells. Hence, the altered smooth muscle cell phenotype in Tsp1(-/-)ApoE(-/-) mice has limited quantitative impact on atherosclerosis, but defective TSP1-mediated phagocytosis enhanced plaque necrotic core formation, accelerating inflammation and macrophage-induced elastin degradation by metalloproteinases, speeding up plaque maturation and vessel wall degeneration.     

Tissue factor and nitric oxide: a controversial relationship!

Tissue factor (TF) is the primary physiological initiator of blood coagulation. TF has a high-affinity for factor (F) VII resulting in the formation of (TF:FVII:FVIIa) bimolecular complex which, in the presence of Ca(2+), increases the enzymatic activity of FVIIa towards its natural substrates, FIX and FX, generating their active forms FIXa and FXa, respectively. This eventually leads to thrombin generation and a fibrin clot formation. Up-regulation of TF in injured blood vessels and atherosclerotic plaque can lead to undesirable vascular thrombosis. Nitric oxide (NO) is a free radical synthesized from L-arginine and molecular oxygen by nitric oxide synthases (NOS). NO participates in diverse physiological and pathophysiological process as an intra or extracellular messenger. A relationship between TF and NO has been proposed. Thus, models of TF regulation by NO has been studied in different cells and experimental animal models, but the results have been conflicting. The premise that NO donors can prevent TF expression in vivo has provided the foundation for a broad field of pharmacotherapeutics in vascular medicine. A new class of drugs combining a statin (inhibitors of coenzyme A reductase) with an NO-donating moiety has been described. The resulting drug, nitrostatin, has been suggested to increase the antithrombotic effects of native statin. However, it is questionable if NO release from these drugs had any significant role on TF inhibition. In summary, care must be taken in drawing conclusions about the relationship between NO and TF. Interpretation of NO studies must take several factors into consideration, including NO bioavailability, its half-life and inactivation, as well as the cell type and experimental model used.     

GLP-1通过调节巨噬细胞泡沫化抑制ApoE-/-小鼠动脉粥样硬化的作用机制研究

目的 研究胰高血糖素样肽1(GLP-1)是否能抑制高脂饮食喂养的载脂蛋白E基因敲除(ApoE-/-)小鼠动脉粥样硬化(AS)进程,从巨噬细胞泡沫化角度探讨相关作用机制.方法 选择6周龄雄性ApoE-/-小鼠40只,随机分为对照组(普通饮食)、模型组(高脂饮食)、GLP-1组(高脂饮食+GLP-1)和GLP-1阻断组(高...     

Repeated exposure to stressors do not accelerate atherosclerosis in ApoE-/- mice

Psychosocial stress is suggested to play a significant role in development of cardiovascular disease. To evaluate the effects of repeated exposure to stress on atherosclerosis in atherosclerosis-prone ApoE(-/-) mice we used five different stressors. We further sought to determine whether stress combined with high salt diet induces dysfunctional neurohormonal regulation and impaired salt excretion, thus amplifying the atherogenic potential of salt. The five stressors were evaluated in male C57BL/6 mice and ApoE(-/-) mice (studies I and II) and then used in female ApoE(-/-) mice to study their effect on atherosclerosis (study III). The mice in study III received standard or high salt diet (8%) alone or in combination with stress for 12 weeks. Urine and plasma were collected for corticosterone and lipid analysis, respectively. Acute blood pressure (BP) and heart rate (HR) responses to stress were measured using telemetry. Plaque burden was assessed in the thoracic aorta and aortic root. Plaque morphology was investigated regarding macrophages and collagen content. Urinary corticosterone chronically increased in stressed mice (P<0.05 control vs. stress, P<0.05 control salt vs. stress salt). BP and HR increased acutely during all stressors (P<0.05). Body weight gain decreased significantly in the stress group (P<0.05 vs. control). However, stress did not alter plasma lipid levels, plaque area or plaque morphology. Increased BP and HR suggest an acute stress-related response in ApoE(-/-) mice. Furthermore, stress chronically decreased body weight gain and increased urinary corticosterone levels. Notably, despite an apparent stress effect, stress affected neither atherogenesis nor plaque morphology.     

冠状动脉内药物支架与非药物支架置入对组织因子和组织因子途径抑制物的影响

目的:了解冠状动脉内支架置入对组织因子(TF)和组织因子途径抑制物(TFPI)的影响;药物支架(雷帕霉素洗脱支架)和非药物支架对TF和TFPI影响是否存在差别。方法:将53例临床特征相似的急性冠状动脉综合征患者分成置入药物支架组(n=24)和非药物支架组两组(n= 29),测定置入支架前、置入后即刻、24小时后、48小时后血液中TF和TFPI的浓度,比较同组中不同时点TF和TFPI的变化以及药物支架组和非药物支架组对应时点的TF和TFPI的变化。结果:药物支架组和非药物支架组患者在置入支架后TF均显著升高;非药物支架组介入后即刻TFPI升高,以后降低至基线值以下,药物支架组也有类似趋势,但两组间对应时点TF和TFPI差别无统计学意义。结论:在现有的药物治疗基础上,置入药物支架和非药物支架对凝血和抗凝系统的影响类似,并不促进系统高凝状态的发生。