Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription
Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription
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DOI：
10.1161/01.cir.0000065220.70220.f7
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发表时间：
2003-04-29
期刊：
影响因子：
37.8
通讯作者：
Yang, CY
中科院分区：
文献类型：
--
作者：
Chen, CH;Jiang, T;Yang, CY
背景-实验修饰的低密度脂蛋白可在体外诱导血管内皮细胞凋亡。促凋亡循环脂蛋白的描述可能会显着提高动脉粥样硬化thrombosis pathophysiology.Methods和Results-Fast蛋白质液相色谱法的LDL样品7无症状，高胆固醇血症患者产生亚组分L-1-L-5在增加电负性的理解。L-4和L-5在血脂正常的样品中不可检测或收集。在牛主动脉EC培养物中，L-5诱导明显的细胞凋亡，L-4有轻微的影响，而高胆固醇血症或血脂正常的L-1-L-3的影响可以忽略不计。与铜氧化LDL相比，L-5仅轻度氧化，尽管其形成共轭二烯的倾向超过了其他亚组分。L-5诱导的细胞凋亡与抑制成纤维细胞生长因子2（FGF-2）的转录，核运行分析评估。通过重组血小板活化因子乙酰水解酶降解L-5中的血小板活化因子（PAF）样脂质可防止FGF-2下调和细胞凋亡。此外，L-5脂质提取物诱导中性粒细胞钙内流的能力丧失后，提取物与PAF乙酰水解酶的预处理。补充FGF-2、用WEB-2086阻断PAF受体（PAFR）以及用百日咳毒素灭活PAFR偶联的G（i）蛋白都有效地减弱了L-5诱导的细胞凋亡。结论-我们的研究结果表明，人高胆固醇血症血浆中存在高度负电、轻度氧化的LDL亚组分，但血脂正常血浆中不存在，可以诱导培养的EC细胞凋亡。新分离的LDL调节FGF-2转录的证据可能为高胆固醇血症中血管EC凋亡的机制提供生理学见解。
Background-Apoptosis of vascular endothelial cells (ECs) can be induced in vitro by experimentally modified LDL. Description of proapoptotic circulating lipoproteins may significantly enhance understanding of atherothrombosis pathophysiology.Methods and Results-Fast protein liquid chromatography of LDL samples from 7 asymptomatic, hypercholesterolemic patients yielded subfractions L-1-L-5 in increasing electronegativity. L-4 and L-5 were not detectable or collectible in normolipidemic samples. In bovine aortic EC cultures, L-5 induced marked apoptosis and L-4 had a mild effect, whereas hypercholesterolemic or normolipidemic L-1-L-3 had negligible effects. Compared with copper-oxidized LDL, L-5 was only mildly oxidized, although its propensity to form conjugated dienes in response to copper exceeded that of other subfractions. L-5-induced apoptosis was associated with suppressed fibroblast growth factor 2 (FGF-2) transcription, as assessed by nuclear run-on analysis. Degrading platelet-activating factor (PAF)-like lipids in L-5 by a recombinant PAF acetylhydrolase prevented both FGF-2 downregulation and apoptosis. Furthermore, the ability of L-5 lipid extract to induce calcium influx into neutrophils was lost after pretreatment of the extract with PAF acetylhydrolase. FGF-2 supplementation, PAF receptor (PAFR) blockade with WEB-2086, and inactivation of PAFR-coupled G(i) protein with pertussis toxin all effectively attenuated L-5-induced apoptosis.Conclusions-Our findings indicate that a highly electronegative, mildly oxidized LDL subfraction present in human hypercholesterolemic but not normolipidemic plasma can induce apoptosis in cultured ECs. The evidence that a freshly isolated LDL species modulates transcription of FGF-2 may provide a physiological insight into the mechanism of vascular EC apoptosis in hypercholesterolemia.