TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells
TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells
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TL1A通过调节血管平滑肌细胞表型抑制apoE缺陷小鼠的动脉粥样硬化
DOI：
10.1074/jbc.ra120.015486
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发表时间：
2020
影响因子：
4.8
通讯作者：
Yang Xiaoxiao
中科院分区：
文献类型：
--
作者：
Zhao Dan;Li Jiaqi;Xue Chao;Feng Ke;Liu Lipei;Zeng Peng;Wang Xiaolin;Chen Yuanli;Li Luyuan;Zhang Zhisong;Duan Yajun;Han Jihong;Yang Xiaoxiao
TNF配体相关分子1A（TL 1A）是一种血管内皮生长抑制剂，可减少新生血管形成。apoE a表达的缺乏导致高胆固醇血症和动脉粥样硬化。在这项研究中，我们确定了TL 1A对apoE缺陷小鼠动脉粥样硬化发展的确切作用及其潜在机制。在12周的促动脉粥样硬化高脂饮食喂养和TL 1A治疗后，收集小鼠主动脉、血清和肝脏样品，并用于评估动脉粥样硬化病变、脂肪肝和相关分子的表达。我们发现TL 1A治疗显著减少病变并增强斑块稳定性。TL 1A通过激活ABC转运蛋白A1（ABCA 1）、ABCG 1的表达和肝脏X受体依赖性胆固醇流出，抑制血管平滑肌细胞（VSMC）而非巨噬细胞来源的泡沫细胞的形成。TL 1A通过激活收缩标志物α平滑肌肌动蛋白的表达和抑制合成标志物骨桥蛋白的表达，或通过减少钙化而抑制成骨细胞样表型，从而减少VSMC从收缩表型向合成表型的转化。此外，TL 1A改善高脂饮食诱导的肝脏脂质代谢紊乱。总之，我们的工作表明TL 1A可以通过调节VSMC/泡沫细胞形成和VSMC表型转换来抑制动脉粥样硬化的发展，并建议进一步研究其治疗动脉粥样硬化的潜力。
TNF ligand-related molecule 1A (TL1A) is a vascular endothelial growth inhibitor to reduce neovascularization. Lack of apoE a expression results in hypercholesterolemia and atherosclerosis. In this study, we determined the precise effects of TL1A on the development of atherosclerosis and the underlying mechanisms in apoE-deficient mice. After 12 weeks of pro-atherogenic high-fat diet feeding and TL1A treatment, mouse aorta, serum, and liver samples were collected and used to assess atherosclerotic lesions, fatty liver, and expression of related molecules. We found that TL1A treatment significantly reduced lesions and enhanced plaque stability. Mechanistically, TL1A inhibited formation of foam cells derived from vascular smooth muscle cells (VSMCs) but not macrophages by activating expression of ABC transporter A1 (ABCA1), ABCG1, and cholesterol efflux in a liver X receptor–dependent manner. TL1A reduced the transformation of VSMCs from contractile phenotype into synthetic phenotypes by activating expression of contractile marker α smooth muscle actin and inhibiting expression of synthetic marker osteopontin, or osteoblast-like phenotype by reducing calcification. In addition, TL1A ameliorated high-fat diet–induced lipid metabolic disorders in the liver. Taken together, our work shows that TL1A can inhibit the development of atherosclerosis by regulating VSMC/foam cell formation and switch of VSMC phenotypes and suggests further investigation of its potential for atherosclerosis treatment.