Mehta Jawahar L, Hu Bo, Chen Jiawei, Li Dayuan
Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, 4301 W Markham St, No. 532, Little Rock, AR 72205, USA.
Arterioscler Thromb Vasc Biol. 2003 Dec;23(12):2203-8. doi: 10.1161/01.ATV.0000094411.98127.5F. Epub 2003 Sep 4.
LOX-1, a novel lectin-like receptor for oxidized LDL (ox-LDL), is expressed in response to ox-LDL, angiotensin II (Ang II), tumor necrosis factor (TNF)-alpha, and other stress stimuli. It is highly expressed in atherosclerotic tissues. Peroxisome proliferator-activated receptor (PPAR)-gamma ligands, such as pioglitazone, exert antiatherosclerotic effects. This study examined the regulation of LOX-1 expression in human coronary artery endothelial cells (HCAECs) by pioglitazone.
Fourth generation HCAECs were treated with ox-LDL, Ang II, or TNF-alpha with or without pioglitazone pretreatment. All 3 stimuli upregulated LOX-1 expression (mRNA and protein). Pioglitazone, in a concentration-dependent manner, reduced LOX-1 expression (P<0.01 versus ox-LDL, Ang II, or TNF-alpha alone). Ox-LDL, Ang II, and TNF-alpha each enhanced intracellular superoxide radical generation, and pioglitazone pretreatment reduced superoxide generation (P<0.01 versus ox-LDL, Ang II, or TNF-alpha). Furthermore, all 3 stimuli upregulated the expression of the transcription factors nuclear factor-kappaB and activator protein-1 (determined by electrophoretic mobility shift assay), and pioglitazone pretreatment reduced this expression (P<0.01 versus ox-LDL, Ang II, or TNF-alpha). To determine the biological significance of pioglitazone-mediated downregulation of LOX-1, we studied monocyte adhesion to ox-LDL-treated HCAECs. Pioglitazone reduced the adhesion of monocytes to activated HCAECs in a fashion similar to that produced by antisense to LOX-1 mRNA.
These observations suggest that the PPAR-gamma ligand pioglitazone reduces intracellular superoxide radical generation and subsequently reduces the expression of transcription factors, expression of the LOX-1 gene, and monocyte adhesion to activated endothelium. The salutary effect of PPAR-gamma ligands in atherogenesis may involve the inhibition of LOX-1 and the adhesion of monocytes to endothelium.
凝集素样氧化型低密度脂蛋白受体1（LOX-1）是一种新型的氧化型低密度脂蛋白（ox-LDL）受体，可响应ox-LDL、血管紧张素II（Ang II）、肿瘤坏死因子（TNF）-α及其他应激刺激而表达。它在动脉粥样硬化组织中高表达。过氧化物酶体增殖物激活受体（PPAR）-γ配体，如吡格列酮，具有抗动脉粥样硬化作用。本研究检测了吡格列酮对人冠状动脉内皮细胞（HCAECs）中LOX-1表达的调控作用。
用ox-LDL、Ang II或TNF-α处理第四代HCAECs，同时或不同时进行吡格列酮预处理。这三种刺激均上调了LOX-1的表达（mRNA和蛋白水平）。吡格列酮呈浓度依赖性地降低LOX-1表达（与单独使用ox-LDL、Ang II或TNF-α相比，P<0.01）。ox-LDL、Ang II和TNF-α均增强了细胞内超氧阴离子的产生，而吡格列酮预处理可减少超氧阴离子的产生（与单独使用ox-LDL、Ang II或TNF-α相比，P<0.01）。此外，这三种刺激均上调了转录因子核因子κB和激活蛋白-1的表达（通过电泳迁移率变动分析测定），而吡格列酮预处理可降低这种表达（与单独使用ox-LDL、Ang II或TNF-α相比，P<0.01）。为确定吡格列酮介导的LOX-1下调的生物学意义，我们研究了单核细胞对ox-LDL处理的HCAECs的黏附情况。吡格列酮以类似于LOX-1 mRNA反义寡核苷酸的方式减少了单核细胞对活化的HCAECs的黏附。
这些观察结果表明，PPAR-γ配体吡格列酮可减少细胞内超氧阴离子的产生，随后降低转录因子的表达、LOX-1基因的表达以及单核细胞对活化内皮的黏附。PPAR-γ配体在动脉粥样硬化发生发展中的有益作用可能涉及对LOX-1的抑制以及单核细胞与内皮的黏附。
