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TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells.
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2020-11-27 , DOI: 10.1074/jbc.ra120.015486
Dan Zhao 1 , Jiaqi Li 2 , Chao Xue 2 , Ke Feng 2 , Lipei Liu 2 , Peng Zeng 2 , Xiaolin Wang 2 , Yuanli Chen 2 , Luyuan Li 3 , Zhisong Zhang 3 , Yajun Duan 4 , Jihong Han 2 , Xiaoxiao Yang 4
Affiliation  

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.

中文翻译:

TL1A 通过调节血管平滑肌细胞的表型来抑制 apoE 缺陷小鼠的动脉粥样硬化。

TNF 配体相关分子 1A (TL1A) 是一种血管内皮生长抑制剂,可减少新血管形成。缺乏 apoE a 表达会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 TL1A 对动脉粥样硬化发展的精确影响以及 apoE 缺陷小鼠的潜在机制。经过 12 周的促动脉粥样硬化高脂饮食喂养和 TL1A 治疗后,收集小鼠主动脉、血清和肝脏样本,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 TL1A 治疗显着减少了病变并增强了斑块稳定性。从机制上讲,TL1A 通过激活 ABC 转运蛋白 A1 (ABCA1)、ABCG1、和胆固醇以肝脏 X 受体依赖性方式流出。TL1A 通过激活收缩标志物 α 平滑肌肌动蛋白的表达并通过减少钙化抑制合成标志物骨桥蛋白或成骨细胞样表型的表达,减少了 VSMC 从收缩表型向合成表型的转化。此外,TL1A 改善了高脂肪饮食引起的肝脏脂质代谢紊乱。总之,我们的工作表明 TL1A 可以通过调节 VSMC/泡沫细胞的形成和 VSMC 表型的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。TL1A 通过激活收缩标志物 α 平滑肌肌动蛋白的表达并通过减少钙化抑制合成标志物骨桥蛋白或成骨细胞样表型的表达,减少了 VSMC 从收缩表型向合成表型的转化。此外,TL1A 改善了高脂肪饮食引起的肝脏脂质代谢紊乱。总之,我们的工作表明 TL1A 可以通过调节 VSMC/泡沫细胞的形成和 VSMC 表型的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。TL1A 通过激活收缩标志物 α 平滑肌肌动蛋白的表达并通过减少钙化抑制合成标志物骨桥蛋白或成骨细胞样表型的表达,减少了 VSMC 从收缩表型向合成表型的转化。此外,TL1A 改善了高脂肪饮食引起的肝脏脂质代谢紊乱。总之,我们的工作表明 TL1A 可以通过调节 VSMC/泡沫细胞的形成和 VSMC 表型的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。
更新日期:2020-11-27
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