Altered Activation of Endothelial Anti- and Proapoptotic Pathways by High-Density Lipoprotein from Patients with Coronary Artery Disease Role of High-Density Lipoprotein-Proteome Remodeling
Altered Activation of Endothelial Anti- and Proapoptotic Pathways by High-Density Lipoprotein from Patients with Coronary Artery Disease Role of High-Density Lipoprotein-Proteome Remodeling
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DOI：
10.1161/circulationaha.112.108753
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发表时间：
2013-02-26
期刊：
影响因子：
37.8
通讯作者：
Landmesser, Ulf
中科院分区：
文献类型：
--
作者：
Riwanto, Meliana;Rohrer, Lucia;Landmesser, Ulf
内皮功能障碍和损伤被认为在冠状动脉疾病（CAD）的进展中起重要作用。来自健康受试者的高密度脂蛋白（HDLHealthy）已被提出发挥内皮抗凋亡作用，这可能代表脂蛋白的重要抗动脉粥样硬化性质。因此，本研究的目的是比较HDLCAD和HDLHealthy对内皮细胞抗凋亡和促凋亡通路的激活的影响，并确定哪些脂蛋白的变化是相关的这些processes.Methods和Results-HDL从稳定的CAD（HDLsCAD），急性冠状动脉综合征（HDLACS），和健康受试者的患者分离。HDLHealthy诱导内皮抗凋亡Bcl-2蛋白Bcl-xL的表达，并在体外和载脂蛋白E缺陷小鼠体内减少内皮细胞凋亡。相反，HDLsCAD和HDLACS不抑制内皮细胞凋亡，未能激活内皮细胞Bcl-xL，并刺激内皮细胞促凋亡途径，特别是p38-丝裂原活化蛋白激酶介导的促凋亡Bcl-2蛋白tBid的激活。HDLHealthy的内皮抗凋亡作用在抑制内皮型一氧化氮合酶和去脂后观察到，但不能完全模仿载脂蛋白A-I或重组HDL，这表明HDL蛋白质组的重要作用。HDL蛋白质组学分析和随后的验证和功能表征表明，减少clusterin和增加载脂蛋白C-III含量的HDLsCAD和HDLACS的机制，导致改变对内皮细胞apoptosis. Conclusions的影响，本研究首次表明，HDLCAD不激活内皮细胞抗凋亡途径，而是刺激潜在的内皮细胞凋亡途径。HDL-蛋白质组重构对HDL的这些改变的功能特性起重要作用。这些发现提供了新的见解机制，导致改变血管HDL在冠心病的影响。（循环。2013; 127：891 - 904.）
Background-Endothelial dysfunction and injury are thought to play an important role in the progression of coronary artery disease (CAD). High-density lipoprotein from healthy subjects (HDLHealthy) has been proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDLCAD and HDLHealthy on the activation of endothelial anti-and proapoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes.Methods and Results-HDL was isolated from patients with stable CAD (HDLsCAD), an acute coronary syndrome (HDLACS), and healthy subjects. HDLHealthy induced expression of the endothelial antiapoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apolipoprotein E-deficient mice in vivo. In contrast, HDLsCAD and HDLACS did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL, and stimulated endothelial proapoptotic pathways, in particular, p38-mitogen-activated protein kinase-mediated activation of the proapoptotic Bcl-2 protein tBid. Endothelial antiapoptotic effects of HDLHealthy were observed after inhibition of endothelial nitric oxide synthase and after delipidation, but not completely mimicked by apolipoprotein A-I or reconstituted HDL, suggesting an important role of the HDL proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin and increased apolipoprotein C-III content of HDLsCAD and HDLACS as mechanisms leading to altered effects on endothelial apoptosis.Conclusions-The present study demonstrates for the first time that HDLCAD does not activate endothelial antiapoptotic pathways, but rather stimulates potential endothelial proapoptotic pathways. HDL-proteome remodeling plays an important role for these altered functional properties of HDL. These findings provide novel insights into mechanisms leading to altered vascular effects of HDL in coronary disease. (Circulation. 2013;127:891-904.)