Feedback regulation of coronary artery disease susceptibility gene ADTRP and LDL receptors LDLR/CD36/LOX-1 in endothelia cell functions involved in atherosclerosis
Feedback regulation of coronary artery disease susceptibility gene ADTRP and LDL receptors LDLR/CD36/LOX-1 in endothelia cell functions involved in atherosclerosis
复制标题
冠心病易感基因ADTRP和LDL受体LDLR/CD36/LOX-1对动脉粥样硬化内皮细胞功能的反馈调节
DOI：
10.1016/j.bbadis.2021.166130
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Qing Wang
中科院分区：
文献类型：
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作者：
Chunyan Luo;Decheng Wang;Weifeng Huang;Yinhong Song;Lisha Ge;Xinyue Zhang;Lixue Yang;Jiao Lu;Xiancong Tu;Qiuyun Chen;Jian Yang;Chengqi Xu;Qing Wang
高水平的低密度脂蛋白胆固醇（LDL）是冠状动脉疾病（CAD）的最重要的危险因素之一，CAD是全球死亡的主要原因。然而，低浓度的LDL可能具有保护作用。全基因组关联研究显示ADTRP基因的变异增加了CAD的风险。在本研究中，我们发现低浓度的氧化LDL诱导ADTRP的表达。进一步的分析表明，LDL受体基因LDLR、CD 36和LOX-1的表达下调可显著下调ADTRP的表达，而LDLR/CD 36/LOX-1的过表达可通过NF-κB途径显著上调ADTRP的表达。与ADTRP一样，LDLR、CD 36和LOX-1也参与了动脉粥样硬化发生的内皮细胞功能。LDLR/CD 36/LOX-1下调可通过增加ICAM-1、VCAM-1、E-selectin和P-selectin的表达，促进单核细胞与内皮细胞的粘附和跨内皮迁移，抑制内皮细胞增殖和迁移，增加内皮细胞凋亡，从而促进动脉粥样硬化的发生。而ADTR和LDLR/CD 36/LOX-1的过度表达则相反。有趣的是，通过NF-κB和AKT途径，ADTRP的过表达显著上调LDLR、CD 36和LOX-1的表达，而ADTRP表达的敲低显著下调LDLR、CD 36和LOX-1的表达。这些数据表明，ADTRP和LDL受体LDLR/CD 36/LOX-1正向相互调节，并形成一个正向调节环，调节内皮细胞功能，从而提供了一个潜在的保护机制，对动脉粥样硬化。我们的研究结果提供了一个新的分子机制，ADTRP和LDLR/CD 36/LOX-1的失调促进动脉粥样硬化和CAD的发展。
A high level of low-density lipoprotein cholesterol (LDL) is one of the most important risk factors for coronary artery disease (CAD), the leading cause of death worldwide. However, a low concentration of LDL may be protective. Genome-wide association studies revealed that variation inADTRPgene increased the risk of CAD. In this study, we found that a low concentration of oxidized-LDL induced the expression ofADTRP. Further analyses showed that knockdown of the expression of LDL receptor genesLDLR,CD36, orLOX-1significantly downregulatedADTRPexpression, whereas overexpression ofLDLR/CD36/LOX-1markedly increasedADTRPexpression through the NF-κB pathway. LikeADTRP,LDLR,CD36andLOX-1were all involved in endothelial cell (EC) functions relevant to the initiation of atherosclerosis. Downregulation ofLDLR/CD36/LOX-1promoted monocyte adhesion to ECs and transendothelial migration of monocytes by increasing expression of ICAM-1, VCAM-1, E-selectin and P-selectin, decreased EC proliferation and migration, and increased EC apoptosis, thereby promoting the initiation of atherosclerosis. Opposite effects were observed with the overexpression ofADTRPandLDLR/CD36/LOX-1in ECs. Interestingly, through the NF-κB and AKT pathways, overexpression ofADTRPsignificantly upregulated the expression ofLDLR,CD36, andLOX-1, and knockdown ofADTRPexpression significantly downregulated the expression ofLDLR,CD36, andLOX-1. These data suggest that ADTRP and LDL receptors LDLR/CD36/LOX-1 positively regulate each other, and form a positive regulatory loop that regulates endothelial cell functions, thereby providing a potential protective mechanism against atherosclerosis. Our findings provide a new molecular mechanism by which deregulation of ADTRP and LDLR/CD36/LOX-1 promote the development of atherosclerosis and CAD.