血凝素样氧化低密度脂蛋白受体-1与动脉粥样硬化

血凝素样氧化低密度脂蛋白受体-1(LOX-1)是氧化低密度脂蛋白(ox-LDL)的特异性受体,结构上属C型血凝素家族,通过介导ox-LDL对血管内皮细胞的损伤参与动脉粥样硬化的形成和发展过程.本文就LOX-1的生物学特性、表达和调节因素及其与动脉粥样硬化的关系进行综述.     

血凝素样氧化低密度脂蛋白受体1——新的药物作用靶点

血凝素样氧化低密度脂蛋白受体1(LOX-1)为最近发现的氧化修饰低密度脂蛋白(ox-LDL)受体,介导内皮细胞摄取代谢ox-LDL,以及ox-LDL对内皮细胞的损伤效应,引起内皮功能失调,导致动脉粥样硬化及相关心血管疾病的发生。适当阻断LOX-1与ox-LDL的结合,将会从源头上阻止ox-LDL对内皮细胞的损伤,从而保护血管功能,防止疾病的发生。所以,LOX-1可能是一个新的药物作用靶点。     

The effect of oxidized low-density lipoprotein (ox-LDL) on radiation-induced endothelial-to-mesenchymal transition

Abstract

Purpose: Radiation-induced cardiovascular disease is a potentially severe side-effect of thoracic radiotherapy treatment. Clinically, this delayed side-effect presents as a form of accelerated atherosclerosis several years after irradiation. As general endothelial dysfunction is known to be an initiating event in radiation-induced vascular damage, we examined the effects of radiation on endothelial cells in radiation-induced atherosclerosis.

Materials and methods: The effects of radiation on human aortic endothelial cells (HAoEC) were assessed by immunoblotting and immunofluorescence assays. Radiation-induced phenotypic changes of endothelial cells (ECs) were examined using atherosclerotic tissues of irradiated apoprotein E null (ApoE^?/?) mice.

Results: Radiation induced the HAoEC to undergo phenotypic conversion to form fibroblast-like cells, called the endothelial-to-mesenchymal transition (EndMT), which leads to the upregulation of mesenchymal cell markers such as alpha-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1), and vimentin, and downregulation of endothelial cell-specific markers such as CD31 and vascular endothelial (VE)-cadherin. Furthermore, compared with low-density lipoprotein (LDL), oxidized low-density lipoprotein (ox-LDL) significantly augmented radiation-induced EndMT in HAoEC. These fibrotic phenotypes of ECs were found in atherosclerotic tissues of irradiated ApoE^?/? mice with increased levels of ox-LDL.

Conclusions: Taken together, these observations suggest that ox-LDL accelerates radiation-induced EndMT and subsequently contributes to radiation-induced atherosclerosis, providing a novel target for the prevention of radiation-induced atherosclerosis.     

Time-dependent effect of statins on platelet function in hypercholesterolaemia

BACKGROUND: Reduction of platelet activity induced by statins has been described as a positive effect exerted by such molecules on vascular thrombotic events. However, the relations among cholesterol (LDL-C) reduction, the timing of the antiplatelet effect, the involved mechanisms and the doses of each statin able to reduce platelet function are not actually well known. The aim of our study was to evaluate the impact of simvastatin (20 mg day-1), atorvastatin (10 mg day-1), fluvastatin (40 mg day-1) and pravastatin (40 mg day-1) on platelet function in hypercholesterolaemic subjects with relation to (LDL-C), oxidized-LDL (ox-LDL) and antiport mechanism modifications. MATERIALS AND METHODS: Sixteen subjects were assigned to each treatment (40 males, 24 females, mean age 48.7 +/- 13.4, LDL-C 5.13 +/- 0,23 mmol L-1) and evaluated for platelet surface P-selectin (P-sel), lipid profile, ox-LDL, platelet-associated ox-LDL (Pox-LDL), platelet cholesterol content, antiport mechanisms, and intracellular and systemic NO synthase every 7 days for one month. RESULTS: Our data show a strong relation between enhanced P-sel and Pox-LDL (r = 0.68, P < 0.01). Simvastatin, atorvastatin, fluvastatin and pravastatin reduce platelet activity after 1, 2, 3 and 4 weeks of treatment, respectively (P < 0.001, P < 0.001, P < 0.01, P < 0.05). Pox-LDL are modulated early by simvastatin, atorvastatin and fluvastatin Pox-LDL (r = 0.66, 0.65 and 0.52; P < 0.001, 0.001 and 0.01, respectively) whereas LDL-C and ox-LDL reductions associated to modifications of antiport activity act later. Moreover, they are the most relevant finding in pravastatin-related subjects. CONCLUSIONS: Our data suggest a different impact of several statins on platelet function, which is initially related to interference with Pox-LDL rather than LDL-C reduction.     

Cholesterol diet and effect of long-term withdrawal on plaque development and composition in the thoracic aorta of New Zealand White rabbits

Aims

Experimental study on plaque progression, regression and composition in atherosclerotic thoracic aorta of hypercholesterolemic rabbits after long-term withdrawal of cholesterol-enriched diet (CED).

Methods

Rabbits were fed 2% cholesterol for 6 weeks followed by withdrawal periods for 15, 23, 34, 68, or 78 weeks. Cholesterol, triglyceride, and phospholipids levels in blood and cholesterol concentrations in aorta were quantified. Plaque size and cellularity, phenotype of macrophages and smooth muscle cells were (immuno)histomorphometrically analyzed in segments of the thoracic aorta.

Results

After 6 weeks of CED, blood cholesterol levels were about 80-fold higher, whereas atherosclerosis and cholesterol content in the thoracic aorta were only minimally increased. However, the latter significantly increased within 15 weeks after cholesterol withdrawal, while serum cholesterol level was still 10-fold increased. Thereafter plaque area and cholesterol content remained almost unchanged until the end of the study despite a long-term normalization of serum cholesterol level after withdrawal of CED. Directly after 6 weeks of CED the densities of macrophages and apoptotic cells within plaques were highest, decreasing after cholesterol withdrawal, whereas, vice versa the density of smooth muscle cells (SMCs) significantly increased.

Conclusion

We suggest that atherosclerotic plaques respond to long-term withdrawal of CED by decrease in number and phenotype of macrophages and increase of SMCs without regression of the lesion size. The cellular changes are suggested to considerably contribute to higher plaque stability.     

新血府逐瘀软胶囊对不稳定型心绞痛血瘀征象及ox-LDL、hs-CRP影响的临床研究

目的探讨新血府逐瘀软胶囊对不稳定型心绞痛(UA)血瘀征象及氧化型低密度脂蛋白(ox-LDL)、高敏C反应蛋白(hs-CRP)的影响。方法60例(UA)患者随机分为治疗组(n=30)和对照组(n=30),另设健康组(n=30)。对照组予以常规治疗(硝酸酯类、钙离子拮抗剂、β-受体阻制剂、血管紧张素转换酶抑制剂及肠溶阿司匹林),治疗组在对照组常规治疗的基础上加服新血府逐瘀软胶囊,两组均用药1个月。分别在治疗前后观察其血瘀征象并检测ox-LDL、hs-CRP水平。结果治疗组与对照组治疗后心绞痛、血瘀征象总有效率比较,差异均有统计学意义;治疗组治疗后血清ox-LDL、hs-CRP的水平均明显低于对照组(P0.05)。结论新血府逐瘀软胶囊可以通过改善UA患者血瘀征象及降低ox-LDL、hs-CRP水平的途径,稳定斑块、抑制脂质过氧化、抗血管内皮炎症、改善内皮功能从而提高对UA的疗效。     

CRP对血管内皮细胞泡沫化及IL-6、MCP-1表达的影响

目的 探讨CRP对血管内皮细胞泡沫化及IL-6、MCP-1表达的影响.方法 不同浓度的CRP(0 mg/L、5 mg/L、10 mg/L、20 mg/L、40 mg/L)与50 mg/L ox-LDL同时作用于人脐静脉内皮细胞,体外培养24h后,采用油红O染色法观察细胞泡沫化情况;采用ELISA方法测定细胞培养上清液中IL-6及MCP-1的浓度.结果 ①随着CRP浓度的增加,人脐静脉内皮细胞内脂滴数量逐渐增多,脂滴逐渐增大,细胞泡沫化程度逐渐加重;②不同浓度CRP(5mg/L、10mg/L、20mg/L、40mg/L)和50mg/L ox-LDL共同刺激24h后,人脐静脉内皮细胞产生IL-6浓度分别为 (33.90±2.64)mg/L、(40.77±3.62)mg/L、(42.19±3.82)mg/L和(44.16±0.57)mg/L,与单独 50mg/L ox-LDL培养的对照组(14.41mg/L±3.38mg/L)比较,有显著性差异(P<0.05);③不同浓度CRP(5mg/L、10mg/L、20mg/L、40mg/L)和50mg/L ox-LDL共同刺激后,人脐静脉内皮细胞产生MCP-1浓度分别为(23.82±3.44)靏/L、(20.11±4.10)靏/L、(19.25±3.67)靏/L、(24.24±3.34)靏/L,与单独 50mg/L ox-LDL培养的对照组(20.36靏/L5.40靏/L) 比较, 无显著性差异(P>0.05).结论 高脂环境下,CRP可加重血管内皮细胞泡沫化,并通过诱导内皮细胞合成IL-6而促进动脉粥样硬化的发生与发展.     

NF-κB对冠心病患者外周血单核细胞LOX-1 mRNA和蛋白表达的影响

目的探讨核因子-κB（NF-κB）对冠心病患者外周血单核细胞凝集素样氧化低密度脂蛋白受体-1（LOX-1）mRNA表达的影响。方法分离收集冠心病患者外周血单核细胞,分为3组:对照组在不含血清的RPMI-1640中孵育24h;ox-LDL组在不含血清的RPMI-1640中加ox-LDL（40μg/ml）孵育24h;PDTC（NF-κB抑制剂）组:先加PDTC(10^-5mol/L)培育1h之后加ox-LDL（40μg/ml）继续孵育24h,之后收集单核细胞及细胞上清液,采用异硫氰酸胍—酚—氯仿抽提法提取总RNA,扩增目的基因LOX-l,并采用ELISA法测定上清液中sLOX-1蛋白浓度。结果与对照组比较,ox-LDL组单核细胞LOX-1 mRNA表达增加（0.304±0.047vs0.813±0.131,P<0.05）,细胞上清液中sLOX-1蛋白含量（ng/ml）增加（7.277±1.979 vs 16.517±2.064,P<0.05）;PDTC组单核细胞LOX-1 mRNA表达及细胞上清液中sLOX-1蛋白含量均增高（分别为0.502±0.140和11.997±1.757,P<0.05）。与ox-LDL组相比,PDTC组单核细胞LOX-1 mRNA表达减少,细胞上清液中sLOX-1蛋白含量显著减少（P<0.05）。结论 ox-LDL可诱导人单核细胞LOX-1表达增加,NF-κB也参与了ox-LDL对LOX-1表达并有促进作用。