LOX-1在动脉粥样硬化中的作用

植物血凝素样氧化低密度脂蛋白受体-1(LOX-1)是与动脉粥样硬化(AS)的发生发展相关联的氧化低密度脂蛋白(ox-LDL)的新型受体,介导ox-LDL诱导的内皮细胞凋亡、单核细胞粘附到内皮,并作用于活化的血小板、导致内皮细胞的损伤.本文就LOX-1的作用机制及其干预措施等作一综述.     

氧化型低密度脂蛋白诱导U937细胞LOX-1的表达及卡托普利的干预

目的:探讨应用氧化型低密度脂蛋白(Ox-LDL)培养的单核巨噬系细胞株U937细胞表面氧化型低密度脂蛋白受体-1(LOX-1)表达的情况,并进一步探讨卡托普利对其表达的影响。方法:应用酶联免疫吸附法(ELISA)和蛋白免疫印迹法(Western blot)检测细胞表面LOX-1的表达。结果:细胞在Ox-LDL培养后LOX-1的表达明显增加(P<0.05),并且随着作用时间的延长和浓度的增加,其表达呈先递增后递减变化,在浓度为100μg/ml,时间为24h时达高峰(0.965±0.413),应用LOX-1阻断剂PIA、角叉菜胶和卡托普利干预后其表达明显减少(P<0.05),结果分别为(0.083±0.024),(0.075±0.019),(0.084±0.025)。结论:Ox-LDL可诱导U937细胞表面LOX-1蛋白质的表达,卡托普利可通过抑制LOX-1的表达,从而抑制Ox-LDL对U937细胞的损伤,起到抗动脉粥样硬化的作用。     

广西巴马小型猪无气管插管全身麻醉模型建立的初探

目的 建立广西巴马小型猪无气管插管的全身麻醉动物模型.方法 选用8头健康广西巴马小型猪,先耳后肌肉注射地西泮10 mg和氯胺酮0.1 g行基础麻醉,建立静脉通道后使用氯胺酮和地西泮间断静脉注射全身麻醉.行泌尿系统手术时根据心率、睫毛反射和疼痛反应调整麻醉深度.结果 该方法麻醉效果理想,试验动物无一头死亡且恢复良好.结论 使用氯胺酮和地西泮对腹部手术的广西巴马小型猪进行间断静脉麻醉的方法效果理想,且安全、简易,值得借鉴.     

广西巴马小型猪浅低温心脏不停跳体外循环模型的建立

目的探讨广西巴马小型猪浅低温心脏不停跳体外循环（ CPB）模型的建立。方法选用32～40 kg健康的广西巴马小型猪13只,10只用于实验,3只用于取血预充。全麻下胸正中切口,心包外法建立体外循环。阻断上、下腔静脉,不阻断主动脉,不灌注心脏停跳液,维持心脏窦性节律空跳。 CPB期间保持心率（ HR）50～80次/min,鼻咽温32～34℃,灌注流量80～100 ml·183; kg-1·183; h-1,平均动脉压（ MAP）60～80 mmHg,红细胞压积（ HCT）20％～25％。结果1只气管插管时误入食道缺氧死亡;1只在分离下腔静脉时破裂出血,经修补和血液回收回输后,生命体征平稳;1只开始转流时出现短暂室颤,未予处理自行转为窦性心率;2只HR＞80次/min,排除麻醉原因后,予机器注入艾司洛尔0.5 mg/kg。 CPB期间尿量（800±177;105）ml,2只有一过性浅红血尿。结论广西巴马小型猪CPB,可以为CPB下不停跳心内手术开展研究提供合适的动物模型。     

高密度脂蛋白防治动脉粥样硬化的新进展

<正> 研究证实,HDL与冠心病风险呈负相关,同时,HDL潜在的抗动脉粥样硬化(AS)功能,使其成为AS性心血管疾病预防和治疗的主要靶向。但是2007年ILLUMINATE研究结果显示,胆固醇酯转运蛋白(CETP)抑制剂torcetrapib虽然能大幅增高HDL-C水平,但是torcetrapib组的死亡人数反而较对照组增多,差异有统计学意义,使研究被迫提前终     

低密度脂蛋白胆固醇自动分析测定与间接计算法结果的比较

目的:探讨F riedew a ld公式的准确性及其在临床中的应用价值。方法:随机选297例不同浓度低密度脂蛋白胆固醇(LDL-C)患者,将其分为三组;TG<4.52 mm o l/L者171例,2.25~4.51 mm o l/L者78例,TG>4.52 mm o l/L者48例,比较自动分析测定法与应用F riedew a ld方法计算的结果。结果:当TG水平<2.25 mm o l/L,2.25~4.51mm o l/L时,测定法与计算法高度相关(r分别为0.97,0.89,P均<0.01),当TG>4.52 mm o l/L时,计算结果与测定的结果相比有比较显著差别,计算偏差接近15%,其r仅为0.78,P<0.05。结论:按F riedew a ld公式计算血LDL-C浓度在低TG浓度条件下有一定的临床应用价值。     

OxLDL对动脉粥样硬化血栓作用研究的进展

动脉粥样硬化(AS)是心血管疾病的主要病理生理基础,也是导致心血管疾病死亡的主要病因.氧化低密度脂蛋白(oxLDL)在AS斑块的发生发展和AS血栓的形成中起重要作用.OxLDL及其组分通过多种途径直接或间接促进促凝血活动及AS血栓的形成.本文就oxLDL及其组分对促进血栓形成的相关细胞和通路的影响作一综述.     

植物凝集素样氧化型低密度脂蛋白受体-1与动脉粥样硬化

植物凝集素样氧化型低密度脂蛋白受体-1（lectin-likeoxidizedlow-densitylipoprotein receptor-1, LOX-1）是氧化型低密度脂蛋白（oxidized low-density lipoproteins, oxLDL）的主要受体之一。近年来的研究表明,LOX-1不仅可以结合、中和以及降解oxLDL,还能与一些非氧化脂蛋白和凋亡的血细胞结合,通过激活血小板、诱导炎症反应、促进血管平滑肌细胞增殖和迁移等多种途径参与动脉粥样硬化进程。文章从LOX-1的结构、功能及其与脂质代谢、动脉粥样硬化发病机制间的关系等方面,对相关研究进展进行了综述。     

三苯氧胺抑制促动脉粥样硬化基因CD36在单核-巨噬细胞的表达

目的 观察抗肿瘤药物三苯氧胺(tamoxifen,Tam)对促动脉粥样硬化基因CD36在单核-巨噬细胞表达的影响。方法 分别以不同浓度Tam(1,5,10 μmol/L)和它的活性代谢物羟-三苯氧胺(OH-Tam)作用于培养的THP-1单核细胞,24 h后观察CD36蛋白在细胞表面的表达;以氧化型低密度脂蛋白(100mg/L)刺激THP-1单核-巨噬细胞CD36表达,并给予Tam或OH-Tam处理,流式细胞术观察CD36的变化。结果 Tam和OH-Tam可降低单核细胞CD36蛋白表达;同时对氧化型低密度脂蛋白引起的单核-巨噬细胞CD36表达上调具有抑制作用。结论 Tam可能通过抑制CD36在单核-巨噬细胞的表面表达来发挥其抗动脉粥样硬化作用。     

A20基因在动脉粥样硬化损伤中对内皮细胞的保护作用

目的　探讨A2 0基因抑制氧化型低密度脂蛋白 (oxidizedlowdensitylipoprotein ,oxLDL)诱导内皮细胞凋亡及相关机制。方法　逆转录 聚合酶链反应检测A2 0基因在oxLDL诱导内皮细胞中的表达。DOTAP脂质体转染pCAGGSEHA2 0和pMAMneo于原代培养的脐静脉内皮细胞 ,经G4 18筛选 ,A2 0表达经免疫荧光鉴定。原位末端标记法、原位杂交检测转染前后oxLDL诱导内皮细胞凋亡情况及同型半胱氨酸蛋白酶 (caspase 3)的表达情况。结果　A2 0基因在oxLDL诱导内皮细胞中不表达。oxLDL诱导内皮细胞凋亡达 2 6 % ,A2 0基因能显著抑制oxLDL诱导的内皮细胞凋亡情况及caspase 3的表达。结论　A2 0基因在动脉粥样硬化的防治中可能有一定作用     

氧化型低密度脂蛋白诱导肝窦内皮细胞植物血凝素样氧化型低密度脂蛋白受体1的表达

目的：探讨植物血凝素样氧化型低密度脂蛋白（ox-LDL）受体1（LOX-1）在肝窦内皮细胞（HSECs）中的表达和ox-LDL对其表达的调控作用。方法使用实时定量聚合酶链反应（RT-PCR）和Western blotting法从基因和蛋白水平检测未经处理HSECs 中LOX-1的表达。应用不同浓度ox-LDL（0、20、40、60、80和100 mg/L）对HSECs作用24 h并应用80 mg/L ox-LDL对HSECs作用不同时间（0、12、24和48 h）,作用后实时定量PCR检测HSECs内LOX-1 mRNA的表达水平,Western blotting法检测细胞内LOX-1蛋白表达。给予80 mg/L ox-LDL干预组多聚肌苷酸250 mg/L作用24 h后,测定LOX-1 mRNA和蛋白的表达。采用单因素方差分析及t检验进行数据分析。结果 LOX-1 mRNA和蛋白在HSECs中均有表达。20～80 mg/L ox-LDL组HSECs中LOX-1 mRNA、蛋白表达水平随ox-LDL剂量增加而升高,与剂量有明显相关性（F＝38.7、3.43,均P＜0.05）。与80 mg/L ox-LDL组相比,100 mg/L ox-LDL 组 LOX-1 mRNA、蛋白表达下降,差异有统计学意义（ t ＝23.75、18.26, P ＜0.05）。80 mg/L ox-LDL对HSECs作用时间在0～24 h时,随着时间延长,LOX-1 mRNA、蛋白表达递增,与ox-LDL作用时间有明显相关性（F＝2.36、0.33,均P＜0.05）。与作用24 h相比,作用48 h组HSECs中LOX-1 mRNA、蛋白表达下降（t＝69.21、36.27,均P＜0.05）。与80 mg/L ox-LDL组相比,多聚肌苷酸组中LOX-1 mRNA和蛋白表达降低,两组差异均有统计学意义（ t＝54.93、28.19,均P＜0.05）。结论LOX-1存在于HSECs。在一定浓度和时间范围内,ox-LDL对HSECs LOX-1的调控作用具有时间和浓度依赖性,而多聚肌苷酸可部分抑制这种效应。     

A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1

One crucial role of endothelium is to keep the innermost surface of a blood vessel antithrombotic. However, the endothelium also expresses prothrombotic molecules in response to various stimuli. The balance between the antithrombotic and prothrombotic nature of the endothelium is lost under certain conditions. During atherosclerosis, the attachment of platelets to the vessel surface has been suggested to promote the proliferation of smooth muscle cells and intimal thickening as well as to affect the prognosis of the disease directly through myocardial infarction and stroke. Dysfunctional endothelium, which is often a result of the action of oxidized low-density lipoprotein (OxLDL), tends to be more procoagulant and adhesive to platelets. Herein, we sought the possibility that the endothelial lectin-like OxLDL receptor-1 (LOX-1) is involved in the platelet-endothelium interaction and hence directly in endothelial dysfunction. LOX-1 indeed worked as an adhesion molecule for platelets. The binding of platelets was inhibited by a phosphatidylserine-binding protein, annexin V, and enhanced by agonists for platelets. These results suggest that negative phospholipids exposed on activation on the surface of platelets are the epitopes for LOX-1. Notably, the binding of platelets to LOX-1 enhanced the release of endothelin-1 from endothelial cells, supporting the induction of endothelial dysfunction, which would, in turn, promote the atherogenic process. LOX-1 may initiate and promote atherosclerosis, binding not only OxLDL but also platelets.     

Diabetic vasculopathy and the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1)

Type 2 diabetes is associated with an increased incidence of coronary heart disease and cardiovascular complications. One crucial step in the initiation and progression of atherosclerosis is the unregulated uptake of oxidized low-density lipoprotein (oxLDL) by vascular wall components through scavenger receptors. Identification of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as the major receptor for oxLDL in endothelial cells has provided a new clue to the mechanisms involved in oxLDL accumulation in the vessel wall. This receptor, by facilitating the uptake of oxLDL, induces endothelial dysfunction and mediates numerous oxLDL-induced proatherogenic effects. Besides endothelial cells, LOX-1 is also expressed by smooth muscle cells and macrophages. In these cells, LOX-1 may function as a scavenger receptor and promote foam cell formation. Notably, LOX-1 is induced by multiple stimuli relevant to atherogenesis and inflammation and is up-regulated in various proatherogenic conditions, including diabetes. As such, activation of vascular cells by oxLDL through LOX-1 may be relevant to the development and progression of human diabetic vasculopathy. This review summarizes recent advances related to the role of LOX-1 in atherosclerosis, its regulation by metabolic and inflammatory factors relevant to diabetes and the impact of these factors on LOX-1-mediated proatherogenic events linked to diabetic vasculopathy.     

Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice

Endothelial dysfunction induced by oxidized low-density lipoprotein (OxLDL) has been implicated in the pathogenesis of atherosclerosis and vasculopathy. Increased expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the receptor for OxLDL in endothelial cells, has been demonstrated in the atherosclerotic plaques from experimental atherosclerotic animal models and human clinical samples. In vitro, activation of LOX-1 alters the expression of several endothelial cell genes that are involved in endothelial dysfunction. To investigate the role of LOX-1 in terms of both endothelial dysfunction and resultant vascular changes, we generated mice overexpressing LOX-1 (LOXtg) in C57BL/6 and apolipoprotein E-null mice (apoEKO) backgrounds. We found that the expression of the transgene was prominent in coronary vessels and cardiomyocytes. The enhancement of OxLDL uptake in LOXtg mice was consistent with the expression level of LOX-1. Under hyperlipidemic conditions, both OxLDL and 8-hydroxy-2'-deoxyguanosine accumulated in the coronary arteries of LOXtg/apoEKO mice. The expression of ICAM-1 and VCAM-1, as well as the number of macrophages around blood vessels, were significantly increased in LOXtg/apoEKO mice compared with control littermates. There were no differences in either the hemodynamic profile or the plasma lipid profile between the 2 groups of animals. LOXtg/apoEKO mice displayed accelerated intramyocardial vasculopathy, and the atheroma-like lesion area was increased 10-fold in the LOXtg/apoEKO mice compared with nontransgenic littermates after 3-weeks on the high-fat diet. Thus, it is demonstrated that LOX-1 overexpression promotes inflammatory intramyocardial vasculopathy in a hyperlipidemic mouse model, and this effect is probably mediated through the endothelial dysfunction induced by overexpression of LOX-1.     

Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion

Angiotensin II via type 1 receptor activation upregulates the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and LOX-1 activation, in turn, upregulates angiotensin II type 1 receptor expression. We postulated that interruption of this positive feedback loop might attenuate the genesis of angiotensin II-induced hypertension and subsequent cardiac remodeling. To examine this postulate, LOX-1 knockout and wild-type mice were infused with angiotensin II or norepinephrine (control for angiotensin II) for 4 weeks. Angiotensin II-, but not norepinephrine-, induced hypertension was attenuated in LOX-1 knockout mice. Angiotensin II-induced cardiac remodeling was also attenuated in LOX-1 knockout mice. Importantly, angiotensin II type 1 receptor expression was reduced, and the expression and activity of endothelial NO synthase were preserved in the tissues of LOX-1 knockout mice given angiotensin II. Reactive oxygen species generation, nicotinamide-adenine dinucleotide phosphate oxidase expression, and phosphorylation of p38 and p44/42 mitogen-activated protein kinases were also much less pronounced in the LOX-1 knockout mice given angiotensin II. These alterations in biochemical and structural abnormalities were associated with preservation of cardiac hemodynamics in the LOX-1 knockout mice. To confirm that fibroblast function is modulated in the absence of LOX-1, cardiac fibroblasts from wild-type and LOX-1 knockout mice were treated with angiotensin II. Indeed, LOX-1 knockout mice cardiac fibroblasts revealed an attenuated profibrotic response on treatment with angiotensin II. These observations provide strong evidence that LOX-1 is a key modulator of the development of angiotensin II-induced hypertension and subsequent cardiac remodeling.     

Weight reduction can decrease circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels in overweight middle-aged men

Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has been reported to be associated with acute coronary syndrome, but its association with obesity has not been elucidated. In this study, we examined whether weight reduction would reduce the serum levels of sLOX-1 in a 12-week weight reduction intervention. Thirty-eight overweight middle-aged men were enrolled in the study, and 32 completed the intervention. The serum level of sLOX-1 was measured using a chemiluminescent enzyme-linked immunoassay. After the intervention program, body weight and the serum level of sLOX-1 decreased significantly (−7.5% ± 4.8% and −72.1% ± 35.9%, respectively). Changes in serum levels of sLOX-1 were positively correlated with changes in body weight (r = 0.54, P = .003), body mass index (r = 0.57, P = .001), body fat mass (r = 0.57, P = .002), total cholesterol (r = 0.41, P = .03), subcutaneous fat area (r = 0.50, P = .007), high-sensitivity C-reactive protein (r = 0.56, P = .002), leptin (r = 0.47, P = .01), and tumor necrosis factor-α (r = 0.32, P = .09); but no correlations were observed with fasting glycemic-related factors (blood glucose, hemoglobin A_1c, and insulin). Changes in body mass index and high-sensitivity C-reactive protein were selected as significant predictors of sLOX-1 changes by multiple regression analyses. These results suggest that LOX-1 induction may be related to adipocyte metabolism, inflammation, and immune response associated with obesity.