Cartilage oligomeric matrix protein fine-tunes disturbed flow-induced endothelial activation and atherogenesis
Cartilage oligomeric matrix protein fine-tunes disturbed flow-induced endothelial activation and atherogenesis
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DOI：
10.1016/j.matbio.2020.10.003
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发表时间：
2021-02-04
期刊：
影响因子：
6.9
通讯作者：
Zhu, Yi
中科院分区：
文献类型：
--
作者：
Lv, Huizhen;Wang, Hui;Zhu, Yi
干扰的流动导致内皮细胞（EC）的炎症反应增加，易于致动脉粥样硬化状态。目前，人们对保护血管系统免受干扰的流动激活EC导致动脉粥样硬化的生理机制知之甚少。了解EC激活中的保护介质可以为动脉粥样硬化提供新的治疗策略。细胞外基质微环境深刻地调节细胞内稳态。软骨寡聚基质蛋白（COMP）是一种非EC驻留的ECM蛋白，在心血管系统中具有多种保护作用。为了确定COMP是否可以防止干扰流激活EC和动脉粥样硬化，我们比较了振荡剪切应力（OSS）诱导的EC活化与各种ECM蛋白包被。纯化的COMP抑制OSS引起的EC活化。与野生型小鼠相比，在生理条件下或病理上，在部分结扎的小鼠颈动脉中，COMP-/-小鼠的主动脉弓中EC激活上调，其中血流受到干扰。从机制上讲，免疫共沉淀、哺乳动物双杂交和FRET测定结果表明COMP通过其C-末端直接结合整联蛋白α 5。我们接下来合成了一种模拟特异性COMP-整联蛋白α 5相互作用的COMP衍生肽模拟物（CCPep 24），并发现CCPep 24在体内保护EC活化和动脉粥样硬化形成。这项研究扩展了我们目前对ECM和血流如何协调微调EC稳态的理解，并揭示了COMP或COMP衍生的肽模拟物对阻断异常整合素α 5活化、炎性EC活化和动脉粥样硬化发病机制的潜在治疗作用。(C)2020 Elsevier B. V.保留所有权利。
Disturbed flow leads to increased inflammatory responses of endothelial cells (ECs) prone to atherogenic state. Currently, little is known about the physiological mechanisms protecting vasculature against disturbed flow-activated ECs leading to atherosclerosis. Understanding the protective mediators involved in EC activation could provide novel therapeutic strategies for atherosclerosis. The extracellular matrix microenvironment profoundly regulates cellular homeostasis. A non-EC resident ECM protein, cartilage oligomeric matrix protein (COMP), has diverse protective roles in the cardiovascular system. To determine whether COMP could protect against disturbed flow-activated EC and atherosclerosis, we compared oscillatory shear stress (OSS) induced EC activation coated with various ECM proteins. Purified COMP inhibited EC activation caused by OSS. EC activation was upregulated in the aortic arch where the flow is disturbed in COMP-/- mice as compared with wild-type mice under physiological conditions or pathologically in partially ligated mouse carotid arteries. Mechanistically, co-immunoprecipitation, mammalian two-hybrid and FRET assay results suggest that COMP bound directly to integrin alpha 5 via its C-terminus. We next synthesized a COMP-derived peptidomimetics (CCPep24) mimicking a specific COMP-integrin alpha 5 interaction and found that CCPep24 protected against EC activation and atherogenesis in vivo. This study extends our current understanding of how ECM and flow coordinately fine-tune EC homeostasis and reveals the potential therapeutic effect of COMP or COMP-derived peptidomimetics on blocking aberrant integrin alpha 5 activation, inflammatory EC activation and atherosclerosis pathogenesis. (C) 2020 Elsevier B.V. All rights reserved.