血管活性肽intermedin调控巨噬细胞炎症反应抑制腹主动脉瘤

Abdominal aortic aneurysm (AAA) is vascular disease characterized by localized dynamic dilatation of the abdominal aorta. (Intermedin(IMD) is a newly discovered paptide in 2004. We reported cardiovascular effects of IMD and found a new fregment peptide IMD1-53 in 2005. We previously found that IMD can inhibit AAA and infiltration of macrophage in animal model. However, its mechanism is unclear. It was reported that inflammation is an important mechanism of AAA. We hypothesizsed that IMD attenuates AAA by regulating macrophage inflammation. This project based on cell and animal model to study :1) Changes of IMD and its receptors and role of IMD in AAA; 2) To determine receptor and key signaling transduction pathways of IMD inhibiting inflammation and regulating M1/M2 macrophage polarization; 3) To elucidate the molecular targets of IMD inhibiting AAA based on migration and proliferation of macrophage, matrix metalloproteinase (MMP), inflammasomes, markers of M1/M2 macrophage polarization, NF-kB, and STAT6; 4) Interaction of IMD and angiotensin II in AAA. To elucidate a new mechanism of IMD inhibiting AAA. To provide a targeted and regulatory target for prevention and treatment of AAA.

腹主动脉瘤（AAA）是以腹主动脉进行性扩张为特点的血管疾病。Intermedin（IMD）是04年发现的活性多肽。05年我室报道了IMD的生物学效应并发现新肽段IMD-1-53。我们前期预实验发现其可抑制AAA和巨噬细胞浸润，但机制不清。慢性炎症是AAA发病的重要机制。我们提出IMD可通过调控巨噬细胞炎症反应抑制AAA。本项目拟进一步研究：1）AAA时IMD及其受体系统变化及在AAA中的作用；2）IMD对炎症及M1 /M2型巨噬细胞表型转换的调节作用及作用的受体和受体后信号转导机制；3）以巨噬细胞迁移、增殖、MMPs、炎症小体、M1/ M2型巨噬细胞分子标志、NF-kB, STAT6为靶点，研究并确证IMD抑制AAA时血管炎症及M1/M2型巨噬细胞表型转换的分子靶点和机制；4）IMD与血管紧张素II在AAA形成中的相互作用。以阐明IMD抑制AAA形成的机制。

腹主动脉瘤（AAA）是以腹主动脉进行性扩张及慢性炎症为主要特点的致死性血管疾病，血管壁透壁性炎症贯穿AAA发病的整个过程。我们前期报道Intermedin（IMD）具有强效和广泛的心血管保护作用，推测IMD可能通过抑制炎症反应抑制AAA发生。本项目在AAA动物模型及VSMC及巨噬细胞上发现外源性及内源性IMD通过减少活性氧生成和VSMC凋亡、降低NADPH氧化酶和基质金属蛋白酶的活性，抑制内质网应激、notch1信号通路介导的炎症和巨噬细胞表型转化抑制AAA发生发展。论证了IMD作为内源性旁/自分泌的心血管调节肽抑制AAA。在IMD转基因和敲除鼠颈动脉损伤模型及VSMC上发现IMD通过调控VSMC表型转化以及抑制VSMC增殖和内质网应激抑制新生内膜形成。在整体动物动脉粥样硬化性血管钙化及VSMCs钙化模型上发现IMD通过抑制内质网应激和炎症反应抑制动脉粥样硬化性血管钙化。同时IMD还可抑制VSMC衰老以及上调Sirt1的表达和去乙酰化酶活性抑制衰老相关的血管钙化。提出IMD是抑制动脉粥样硬化性血管钙化以及衰老相关血管钙化的内源性生物活性小分子调节肽。IMD还可以通过上调Klotho以及抑制内质网应激和炎症抑制心肌肥厚及心脏纤维化。项目按计划完成，阐明了IMD通过抑制炎症、巨噬细胞表型转化、调控氧化应激和内质网应激抑制AAA的发生发展，揭示了IMD抑制巨噬细胞表型转化和炎症抑制AAA的分子机制，为AAA的早期防治提供潜在的新靶点。