Oxidatively Modified LDL Suppresses Lymphangiogenesis via CD36 Signaling.
Oxidatively Modified LDL Suppresses Lymphangiogenesis via CD36 Signaling.
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DOI：
10.3390/antiox10020331
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发表时间：
2021-02-23
期刊：
影响因子：
--
通讯作者：
Csányi G
中科院分区：
文献类型：
--
作者：
Singla B;Lin HP;Ahn W;White J;Csányi G
血浆来源的LDL的动脉蓄积及其随后的氧化有助于动脉粥样硬化。淋巴管（LV）介导的动脉胆固醇清除已被证明可以减少动脉粥样硬化病变的形成。然而，在动脉粥样硬化血管中调节LV密度和功能的确切机制仍有待确定。本研究旨在探讨天然低密度脂蛋白（nLDL）和氧化低密度脂蛋白（oxLDL）在调节淋巴管生成中的作用及其分子机制。免疫印迹和免疫染色实验表明，在人类动脉粥样硬化动脉氧化低密度脂蛋白表达增加。此外，在LV主要存在的外膜层中检测到oxLDL水平升高。用oxLDL处理人淋巴管内皮细胞（LEC），可抑制体外小管形成，而nLDL则可促进小管形成，体内Matrigel法也观察到类似的结果。小鼠CD 36缺失及其siRNA介导的LEC敲低可阻止oxLDL诱导的淋巴管生成抑制。此外，oxLDL通过CD 36受体抑制LEC的细胞周期，下调AKT和eNOS表达，并增加p27水平。总之，这些结果表明oxLDL通过CD 36介导的AKT/eNOS通路和细胞周期的调节来抑制淋巴管生成。这些发现表明，治疗性阻断LEC CD 36可能促进动脉淋巴管生成，导致增加胆固醇从动脉壁的清除和减少动脉粥样硬化。
Arterial accumulation of plasma-derived LDL and its subsequent oxidation contributes to atherosclerosis. Lymphatic vessel (LV)-mediated removal of arterial cholesterol has been shown to reduce atherosclerotic lesion formation. However, the precise mechanisms that regulate LV density and function in atherosclerotic vessels remain to be identified. The aim of this study was to investigate the role of native LDL (nLDL) and oxidized LDL (oxLDL) in modulating lymphangiogenesis and underlying molecular mechanisms. Western blotting and immunostaining experiments demonstrated increased oxLDL expression in human atherosclerotic arteries. Furthermore, elevated oxLDL levels were detected in the adventitial layer, where LV are primarily present. Treatment of human lymphatic endothelial cells (LEC) with oxLDL inhibited in vitro tube formation, while nLDL stimulated it. Similar results were observed with Matrigel plug assay in vivo. CD36 deletion in mice and its siRNA-mediated knockdown in LEC prevented oxLDL-induced inhibition of lymphangiogenesis. In addition, oxLDL via CD36 receptor suppressed cell cycle, downregulated AKT and eNOS expression, and increased levels of p27 in LEC. Collectively, these results indicate that oxLDL inhibits lymphangiogenesis via CD36-mediated regulation of AKT/eNOS pathway and cell cycle. These findings suggest that therapeutic blockade of LEC CD36 may promote arterial lymphangiogenesis, leading to increased cholesterol removal from the arterial wall and reduced atherosclerosis.
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影响因子：
4
作者：
Chong, Curtis R.;Xu, Jing;Liu, Jun O.
通讯作者：
Liu, Jun O.
影响因子：
15.9
作者：
Febbraio, M;Podrez, EA;Silverstein, RL
通讯作者：
Silverstein, RL
影响因子：
37.8
作者：
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通讯作者：
Collen, D
DOI：
10.1016/j.jcmgh.2020.09.007
发表时间：
2021
影响因子：
7.2
作者：
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通讯作者：
Jirón Tamburini BA
影响因子：
20.1
作者：
Chen, Kan;Febbraio, Maria;Silverstein, Roy L.
通讯作者：
Silverstein, Roy L.