EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling
EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling
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DOI：
10.1152/japplphysiol.00879.2009
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发表时间：
2010-06-01
影响因子：
3.3
通讯作者：
Lee, Shin-Da
中科院分区：
文献类型：
--
作者：
Ou, Hsiu-Chung;Song, Tuzz-Ying;Lee, Shin-Da
Ou HC，Song TY，Yeh YC，Huang CY，Yang SF，Chiu TH，Tsai KL，Chen KL，Wu YJ，Tsai CS，Chang LY，Kuo WW，Lee SD.表没食子儿茶素没食子酸酯通过抑制脂氧合酶-1介导的信号传导来保护氧化低密度脂蛋白诱导的内皮功能障碍。J Appl Physiol 108：1745-1756，2010.首次出版于2010年3月4日; doi：10.1152/japplphysiol. 00879.2009.-凝集素样氧化低密度脂蛋白受体-1（LOX-1）最初被鉴定为内皮细胞中氧化低密度脂蛋白（oxLDL）的主要受体，在血管疾病的病理学中起主要作用。在一些流行病学研究中，饮用绿色茶与降低心血管死亡率有关。在本研究中，我们假设茶中最丰富的多酚化合物表没食子儿茶素-3-没食子酸酯（EGCG）可以通过调节LOX 1调节的细胞信号转导来下调内皮功能障碍的参数。在培养的人脐静脉内皮细胞（HUVEC）中，暴露于oxLDL（130 μ g/ml），导致LOX-1在RNA和蛋白水平表达增加，通过加入EGCG或DPI（一种众所周知的黄素蛋白抑制剂），提示NADPH氧化酶参与。此外，oxLDL迅速激活Rac-1和p47（phox）的膜转位，并随后诱导ROS的产生，这是明显抑制预处理与EGCG或抗LOX-1单克隆抗体。氧化低密度脂蛋白还增加p38 MAPK磷酸化和减少Akt氨基末端区域的磷酸化，在约30 min时诱导最大，并在1 h内诱导NF-κ B磷酸化，导致氧化还原敏感性信号传导。此外，oxLDL减少内皮型一氧化氮合酶（eNOS）的表达，增强内皮素-1和粘附分子（ICAM，E-选择素，单核细胞趋化蛋白-1）的表达，并增加单核细胞THP-1细胞粘附HUVEC。然而，用EGCG预处理在所有事件中都产生了显着的细胞保护作用。这些数据表明，EGCG抑制oxLDL诱导的LOX-1介导的信号通路，至少部分是通过抑制NADPH氧化酶和随后的ROS增强的LOX-1表达，这有助于进一步的ROS产生和随后通过p38 MAPK通路激活NF-κ B。这项研究的结果可能提供了一个可能的分子机制，EGCG抑制oxLDL介导的血管内皮功能障碍的见解。
Ou HC, Song TY, Yeh YC, Huang CY, Yang SF, Chiu TH, Tsai KL, Chen KL, Wu YJ, Tsai CS, Chang LY, Kuo WW, Lee SD. EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1- mediated signaling. J Appl Physiol 108: 1745-1756, 2010. First published March 4, 2010; doi:10.1152/japplphysiol. 00879.2009.-Lectin- like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein (oxLDL) in endothelial cells, plays a major role in the pathology of vascular diseases. Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. In the present study, we hypothesized that the most abundant polyphenolic compound in tea, epigallocatechin-3-gallate (EGCG), can down-regulate parameters of endothelial dysfunction by modulating LOX1-regulated cell signaling. In cultured human umbilical vein endothelial cells (HUVECs), exposure to oxLDL (130 mu g/ml), which led to an increase in LOX-1 expression at the RNA and protein levels, was abrogated by addition of EGCG or DPI, a well-known inhibitor of flavoproteins, suggesting the involveme nt of NADPH oxidase. Furthermore, oxLDL rapidly activated the membrane translocation of Rac-1 and p47(phox) and the subsequent induction of ROS generation, which was suppressed markedly by pretreatment with EGCG or anti-LOX-1 monoclonal antibody. OxLDL also increased p38 MAPK phosphorylation and decreased phosphorylation of the amino-terminal region of Akt, with maximal induction at about 30 min, and NF-kappa B phosphorylation within 1 h, resulting in redox-sensitive signaling. In addition, oxLDL diminished the expression of endothelial nitric oxide synthase (eNOS), enhanced the expression of endothelin-1 and adhesion molecules (ICAM, E-selectin, and monocyte chemoattractant protein-1), and increased the adherence of monocytic THP-1 cells to HUVECs. Pretreatment with EGCG, however, exerted significant cyto-protective effects in all events. These data suggest that EGCG inhibits the oxLDL-induced LOX-1-mediated signaling pathway, at least in part, by inhibiting NADPH oxidase and consequent ROS-enhanced LOX-1 expression, which contributes to further ROS generation and the subsequent activation of NF-kappa B via the p38 MAPK pathway. Results from this study may provide insight into a possible molecular mechanism by which EGCG suppresses oxLDL-mediated vascular endothelial dysfunction.