LOX-1，一种从内皮细胞中识别出的氧化型低密度脂蛋白受体：对内皮功能障碍和动脉粥样硬化的影响。,Pharmacology & Therapeutics

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LOX-1，一种从内皮细胞中识别出的氧化型低密度脂蛋白受体：对内皮功能障碍和动脉粥样硬化的影响。
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2002-08-07 , DOI: 10.1016/s0163-7258(02)00236-x
Mingyi Chen ₁ , Tomoh Masaki , Tatsuya Sawamura

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凝集素样氧化低密度脂蛋白（LDL）受体1（LOX-1）最初被确定为内皮细胞中氧化LDL（OxLDL）的主要受体。还观察到其在巨噬细胞和平滑肌细胞中的诱导表达。LOX-1是II型膜蛋白，在细胞外C端具有典型的C型凝集素结构。它可以被细胞外近膜区域的未知蛋白酶切割，从而释放出可溶的LOX-1形式。LOX-1的胞外域通过N-联糖基化进行翻译后修饰。诱变研究表明，LOX-1的凝集素结构域是识别LOX-1配体的功能域。跨越凝集素结构域的C末端残基和几个保守的带正电荷的残基对于OxLDL结合至关重要。OxLDL激活LOX-1会引起内皮细胞改变，其特征是通过增加活性氧来激活核因子-κB，随后诱导粘附分子和内皮细胞凋亡。在体外，LOX-1的表达是由许多炎性细胞因子，氧化应激，血液动力学刺激和OxLDL诱导的。在体内，该表达在促动脉粥样硬化环境中（包括高血压，高脂血症和糖尿病）增强，并且实际上在动脉粥样硬化和肾小球硬化病变中积累。LOX-1结合与动脉粥样硬化发病机制有关的多种配体。除OxLDL外，LOX-1还可以识别凋亡/老化的细胞，活化的血小板和细菌，这意味着多种生理功能。在一起所有这些发现都支持LOX-1对血管疾病，尤其是动脉粥样硬化的发病机制的可能贡献。开发LOX-1拮抗剂可能是治疗血管疾病的好方法。

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LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis.

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) was initially identified as the major receptor for oxidized LDL (OxLDL) in endothelial cells. Its inducible expression in macrophages and smooth muscle cell was also observed. LOX-1 is a Type II membrane protein with a typical C-type lectin structure at the extracellular C-terminus. It can be cleaved by an unknown protease at the extracellular juxtamembrane region to release the soluble form of LOX-1. The extracellular domains of LOX-1 are post-translationally modified by N-linked glycosylation. Mutagenesis studies revealed that the lectin domain of LOX-1 is the functional domain that recognizes the LOX-1 ligand. The C-terminal end residues and several conserved positively charged residues spanning the lectin domain are essential for OxLDL binding. LOX-1 activation by OxLDL causes endothelial changes that are characterized by activation of nuclear factor-kappaB through an increased reactive oxygen species, subsequent induction of adhesion molecules, and endothelial apoptosis. In vitro, expression of LOX-1 is induced by many inflammatory cytokines, oxidative stress, hemodynamic stimuli, and OxLDL. In vivo, the expression is enhanced in pro-atherogenic settings including, hypertension, hyperlipidemia, and diabetes, and, indeed, is accumulated in the atherosclerotic and glomerulosclerotic lesions. LOX-1 binds multiple classes of ligands that are implicated in the pathogenesis of atherosclerosis. Besides OxLDL, LOX-1 can recognize apoptotic/aged cells, activated platelets, and bacteria, implying versatile physiological functions. Taken together, all these findings support the possible contribution of LOX-1 to the pathogenesis of vascular disorders, particularly atherosclerosis. Development of antagonists for LOX-1 might be a good therapeutic approach to vascular diseases.

更新日期：2019-11-01

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