Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, China.
School of Pharmacy and Life Science College, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, China.
J Lipid Res. 2019 Dec;60(12):2020-2033. doi: 10.1194/jlr.RA119000100. Epub 2019 Oct 29.
CXC chemokine ligand 12 (CXCL12) is a member of the CXC chemokine family and mainly acts on cell chemotaxis. CXCL12 also elicits a proatherogenic role, but the molecular mechanisms have not been fully defined yet. We aimed to reveal if and how CXCL12 promoted atherosclerosis via regulating lipid metabolism. In vitro, our data showed that CXCL12 could reduce ABCA1 expression, and it mediated cholesterol efflux from THP-1-derived macrophages to apoA-I. Data from the luciferase reporter gene and chromatin immunoprecipitation assays revealed that transcription factor 21 (TCF21) stimulated the transcription of ABCA1 via binding to its promoter region, which was repressed by CXCL12. We found that CXCL12 increased the levels of phosphorylated glycogen synthase kinase 3β (GSK3β) and the phosphorylation of β-catenin at the Thr120 position. Inactivation of GSK3β or β-catenin increased the expression of TCF21 and ABCA1. Further, knockdown or inhibition of CXC chemokine receptor 4 (CXCR4) blocked the effects of CXCL12 on TCF21 and ABCA1 expression and the phosphorylation of GSK3β and β-catenin. In vivo, the overexpression of CXCL12 in Apoe mice via lentivirus enlarged the atherosclerotic lesion area and increased macrophage infiltration in atherosclerotic plaques. We further found that the overexpression of CXCL12 reduced the efficiency of reverse cholesterol transport and plasma HDL-C levels, decreased ABCA1 expression in the aorta and mouse peritoneal macrophages (MPMs), and suppressed cholesterol efflux from MPMs to apoA-I in Apoe mice. Collectively, these findings suggest that CXCL12 interacts with CXCR4 and then activates the GSK-3β/β-catenin/TCF21 signaling pathway to inhibit ABCA1-dependent cholesterol efflux from macrophages and aggravate atherosclerosis. Targeting CXCL12 may be a novel and promising strategy for the prevention and treatment of atherosclerotic cardiovascular diseases.
CXC 趋化因子配体 12（CXCL12）是 CXC 趋化因子家族的成员，主要作用于细胞趋化性。CXCL12 还具有促动脉粥样硬化作用，但分子机制尚未完全确定。我们旨在揭示 CXCL12 是否以及如何通过调节脂质代谢促进动脉粥样硬化。在体外，我们的数据表明，CXCL12 可以降低 ABCA1 的表达，并介导 THP-1 衍生的巨噬细胞中的胆固醇流出到 apoA-I。荧光素酶报告基因和染色质免疫沉淀测定的数据显示，转录因子 21（TCF21）通过结合其启动子区域刺激 ABCA1 的转录，而 CXCL12 则抑制该转录。我们发现，CXCL12 增加了磷酸化糖原合酶激酶 3β（GSK3β）和 β-连环蛋白 Thr120 位磷酸化的水平。GSK3β 或 β-连环蛋白失活会增加 TCF21 和 ABCA1 的表达。此外，敲低或抑制 CXC 趋化因子受体 4（CXCR4）可阻断 CXCL12 对 TCF21 和 ABCA1 表达以及 GSK3β 和 β-连环蛋白磷酸化的影响。在体内，通过慢病毒过表达 Apoe 小鼠中的 CXCL12 会扩大动脉粥样硬化病变面积并增加动脉粥样硬化斑块中的巨噬细胞浸润。我们进一步发现，CXCL12 的过表达降低了胆固醇逆转运的效率和血浆高密度脂蛋白胆固醇（HDL-C）水平，降低了主动脉和小鼠腹腔巨噬细胞（MPMs）中的 ABCA1 表达，并抑制了 Apoe 小鼠 MPMs 中胆固醇流出到 apoA-I。总之，这些发现表明，CXCL12 与 CXCR4 相互作用，然后激活 GSK-3β/β-连环蛋白/TCF21 信号通路，抑制巨噬细胞中 ABCA1 依赖性胆固醇流出，并加重动脉粥样硬化。靶向 CXCL12 可能是预防和治疗动脉粥样硬化性心血管疾病的一种新的有前途的策略。
