载脂蛋白相关蛋白 7 基因的一个与冠心病相关的变异对血管内皮细胞血管生成的影响。
Effect of a coronary-heart-disease-associated variant of ADAMTS7 on endothelial cell angiogenesis.
机构信息
First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; William Harvey Research Institute, Queen Mary University of London, London, UK.
William Harvey Research Institute, Queen Mary University of London, London, UK; Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
出版信息
Atherosclerosis. 2020 Mar;296:11-17. doi: 10.1016/j.atherosclerosis.2020.01.015. Epub 2020 Jan 21.
BACKGROUND AND AIMS
Recent studies have unveiled an association between ADAMTS7 gene variation and coronary artery disease (CAD) caused by atherosclerosis. We investigated if the ADAMTS7 Serine214-to-Proline substitution arising from a CAD-associated variant affected angiogenesis, since neovascularization plays an important role in atherosclerosis.
METHODS AND RESULTS
ADAMTS7 knockdown in vascular endothelial cells (ECs) attenuated their angiogenesis potential, whereas augmented ADAMTS7-Ser214 expression had the opposite effect, leading to increased ECs migratory and tube formation ability. Proteomics analysis showed an increase in thrombospondin-1, a reported angiogenesis inhibitor, in culture media conditioned by ECs with ADAMTS7 knockdown and a decrease of thrombospondin-1 in media conditioned by ECs with ADAMTS7-Ser214 overexpression. Cleavage assay indicated that ADAMTS7 possessed thrombospondin-1 degrading activity, which was reduced by the Ser214-to-Pro substitution. The pro-angiogenic effect of ADAMTS7-Ser214 diminished in the presence of a thrombospondin-1 blocking antibody.
CONCLUSIONS
The ADAMTS7 Ser217-to-Pro substitution as a result of ADAMTS7 polymorphism affects thrombospondin-1 degradation, thereby promoting atherogenesis through increased EC migration and tube formation.
背景与目的
最近的研究揭示了 ADAMTS7 基因变异与动脉粥样硬化引起的冠心病（CAD）之间的关联。我们研究了源于 CAD 相关变异的 ADAMTS7 丝氨酸 214 至脯氨酸取代是否会影响血管生成，因为新生血管化在动脉粥样硬化中起着重要作用。
方法与结果
在血管内皮细胞（ECs）中敲低 ADAMTS7 会减弱其血管生成潜力，而增强的 ADAMTS7-Ser214 表达则会产生相反的效果，导致 ECs 的迁移和管形成能力增加。蛋白质组学分析表明，ADAMTS7 敲低的 ECs 条件培养基中血栓素-1（一种已知的血管生成抑制剂）增加，而 ADAMTS7-Ser214 过表达的 ECs 条件培养基中血栓素-1 减少。裂解实验表明 ADAMTS7 具有血栓素-1 降解活性，而 Ser214 至 Pro 取代会降低其活性。在存在血栓素-1 阻断抗体的情况下，ADAMTS7-Ser214 的促血管生成作用减弱。
结论
ADAMTS7 多态性导致的 ADAMTS7 Ser217-to-Pro 取代会影响血栓素-1 的降解，从而通过增加 EC 迁移和管形成促进动脉粥样硬化形成。
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