Oxidized High-Density Lipoprotein Impairs Endothelial Progenitor Cells' Function by Activation of CD36-MAPK-TSP-1 Pathways
Oxidized High-Density Lipoprotein Impairs Endothelial Progenitor Cells' Function by Activation of CD36-MAPK-TSP-1 Pathways
复制标题
氧化高密度脂蛋白通过激活 CD36-MAPK-TSP-1 途径损害内皮祖细胞的功能。
DOI：
10.1089/ars.2013.5743
复制
发表时间：
2015-02-01
影响因子：
6.6
通讯作者：
Wu, Zonggui
中科院分区：
文献类型：
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作者：
Wu, Jianxiang;He, Zhiqing;Wu, Zonggui
目标
高密度脂蛋白(HDL)水平与心血管事件呈负相关，这是由于对血管壁和干细胞的保护作用，而这些细胞容易受到氧化修饰，从而导致潜在的促动脉粥样硬化效应。我们提出氧化型高密度脂蛋白(ox-HDL)可能导致内皮祖细胞功能障碍，并对其机制进行了探讨。
结果
氧化型高密度脂蛋白可增加EPC的细胞凋亡率和细胞内的活性氧水平，但减少EPC的迁移、血管生成和胆固醇外流，并呈剂量依赖性。氧化-高密度脂蛋白刺激后，p38丝裂原活化蛋白激酶和核因子-高密度脂蛋白B被激活，同时上调了血小板反应素-1(TSP-1)的表达，但不影响血管内皮生长因子。短发夹状RNA介导的CD36基因敲除或普罗布考可显著减弱氧化-高密度脂蛋白的作用。体内实验数据以及冠心病(CAD)患者或冠心病和2型糖尿病患者的OX-HDL值与循环中EPC数量的负相关也支持这一观点。同时，从这类患者中分离出的高密度脂蛋白可以显著提高培养的EPC的caspase3活性，进一步支持了我们的建议。
创新
这是迄今为止关于氧化-高密度脂蛋白如何损害内皮祖细胞功能的最完整的研究，它涉及CD36-p38MAPK-TSP-1通路的激活，不仅从临床上证明了氧化-高密度脂蛋白与循环内皮细胞的反向关系，而且从患者血清中分离出的高密度脂蛋白具有促细胞凋亡的作用。
结论
CD36-p38MAPK-TSP-1通路的激活参与了氧化高密度脂蛋白致内皮祖细胞功能障碍的病理过程，这可能是慢性缺血性疾病血管生成障碍的潜在病因之一。
AIMS
High-density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which are susceptible to oxidative modifications and then lead to potential pro-atherosclerotic effects. We proposed that oxidized HDL (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms.
RESULTS
ox-HDL was shown to increase apoptosis and intracellular reactive oxygen species levels, but to reduce migration, angiogenesis, and cholesterol efflux of EPCs in a dose-dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-κB were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 (TSP-1) expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with short hairpin RNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inverse correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases (CAD) or CAD and type 2 diabetes also supported it. Meanwhile, HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, further supporting our proposal.
INNOVATION
This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic but also pro-apoptotic effects of HDL separated from patients' serum.
CONCLUSION
Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of the potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease.