CD146在动脉粥样硬化发展中的作用机制研究

Atherosclerosis (AS) is a chronic non-resolving inflammatory disease of the arterial wall. Although the retention of macrophages and smooth muscle cell migration into the arterial wall has long been recognized as a fundamental step in the creation of the chronic inflammatory milieu that underlies atherosclerosis, but the key molecules and the mechanisms that regulate this process are not well understood. Our research has been focusing on chronic non-resolving inflammation as long-term studies. We discovered that (1) CD146 is expressed on macrophages of the inflammatory sites; (2) CD146 is involved in the development of chronic inflammation, and (3) anti-CD146 antibody has therapuetic effect on chronic non-resolving inflammation. Therefore, we propose that CD146 facilitates the progression of this non-resolving inflammation. In this study, we will systemically investigate the role of CD146 in atherosclerosis. Firstly, we will explore the role of CD146 on macrophage activation, lipid uptake and emigration/retention in the lesional plaques under high-fat environment. Secondly, using CD146 knockout mice and mouse model of atherosclerosis, we will study the effect of anti-CD146 therapy on lesional macrophage accumulation and plaque progression. Thirdly, by analyzing human atherosclerotic plaque, we will investigate the correlation between macrophage CD146 expression and plaque invulnerability. Our study will not only identify a new target for the treatment of atherosclerosis, but also provides a novel molecular mechanism for chronic non-resolving inflammation and broaden the clinical application of anti-CD146 antibody.

动脉粥样硬化是累及全身大动脉的慢性非可控性血管炎症病变。虽然巨噬细胞募集和平滑肌细胞的迁移被认为是形成动脉粥样硬化炎症微环境的基础，但调节这一重要过程的机制尚未阐明。申请者对非可控性炎症的研究发现（1）CD146在炎症部位免疫细胞上表达，（2）CD146参与慢性炎症发展，（3）CD146抗体能治疗慢性炎症。因此，大胆提出了CD146是促进动脉粥样硬化发展的关键分子。本研究将系统探索CD146在动脉粥样硬化发展中的作用。通过相互作用方法，揭示CD146对巨噬细胞信号通路活化、脂质吞噬及向斑块外迁移的影响；利用CD146敲除及动脉粥样硬化小鼠模型，观察抗CD146抗体治疗对动脉粥样硬化斑块中巨噬细胞募集和斑块进展的影响。通过分析动脉粥样硬化临床标本，证实CD146表达跟斑块不稳定性的相关性。本研究将提供治疗动脉粥样硬化的新靶标，为非可控炎症提供新机制，并拓宽抗CD146抗体的临床应用。

动脉粥样硬化是累及全身大动脉的慢性非可控性血管炎症病变。虽然巨噬细胞募集被认为是形成动脉粥样硬化炎症微环境的基础，但调节这一重要过程的机制尚未阐明。申请者在本基金的资助下，经过三年探索研究，项目取得了一系列原创性进展。申请者首次提出巨噬细胞CD146是促进动脉粥样硬化发展的关键分子。我们深入研究了CD146调控动脉粥样硬化发展的作用机制，揭示了CD146介导巨噬细胞脂质吞噬、炎症反应以及迁移的调控机制，主要发现有：（1）阐述了CD146表达与斑块不稳定性的相关，并揭示了CD146在高脂微环境中的表达调控机制，发现oxLDL通过活化NF-kB促进CD146表达。（2）揭示了CD146调控巨噬细胞脂质吞噬的分子机制；发现CD146调控巨噬细胞CD36内化和oxLDL摄入，促进泡沫细胞形成。（3）证明了CD146在调控巨噬细胞炎症相关信号激活和在斑块中聚集的分子机制。（4）在动脉粥样硬化模型ApoE-/-小鼠中，发现CD146是该疾病治疗的新靶点。总之，本研究以动脉粥样硬化发生机制为导向，深入探索了CD146调控巨噬细胞聚集的分子机制，阐明了CD146作为关键节点促进泡沫细胞形成、活化炎症信号通路，并促进斑块发展的新机制，为动脉粥样硬化疾病的治疗提供了新的靶点。