主动脉瘤/夹层发生、发展及转归的机制和干预措施研究

Aortic aneurysm and dissection are common critical vascular disease, and mainly characterized as medial damage. It has been known that SM22α inhibits vascular inflammatory process, maintains vascular homeostasis. Supported by the major research program on vascular diseases, we found that the disruption of SM22α is involved in almost all pathological processes related to aortic aneurysm and dissection. IMD is a vasoactive peptide to inhibit oxidative stress. The miR-126/EGFL7 is involved in regulation of vascular integrity. We hypothesized that the homeostasis of the cytoskeleton dynamics of vascular smooth muscle cells is a key and target for development and intervention of aortic aneurysm and dissection. The miR-126 and circ Sirt1 inhibit the development of AAA by synergistic action with anti-inflammatory genes. IMD-induced SM22α activation is critical for prevention of vascular media reconstruction. This project aimed to investigate the endogenous anti-injury defense system of vascular cells in respond to pathological stimuli and its relationship with the prognosis of vascular diseases during aortic aneurysm formation. We are going to focus on the expression and roles of miR-126-circ Sirt1-SM22α-IMD in vascular cells in response to pathological stimuli. It will be elucidated that the mechanism underlying the exosome-mediated interaction of vascular cells, and the effects on the homeostasis and remodeling of vascular extracellular matrix. Next, the project was designed to explore the functions of SM circ Sirt1 in the inflammatory response of endothelial cells and microphages, and the mechanism by which they represent a potential mode of intercellular communication throughout the entire circulatory system. The goals of the project are to determine that miR-126-circ Sirt1 -SM22α-IMD is an endogenous molecular network for resistance to vascular inflammatory damage, and may be required for synergism response of vascular cells and vascular orderly remodeling. We assess the clinical significance of SM22α as a potential early diagnostic biomarker in the patients with critical vascular diseases.

主动脉瘤/夹层是致死率极高的危重血管疾病。本计划资助下，平滑肌SM22α、非编码RNA、血管活性肽IMD的抗氧化应激机制研究已取得重要进展；证实缺失SM22α可通过细胞骨架紊乱而激活与主动脉瘤/夹层相关的所有病理过程。但病理状态下三者协同发挥血管保护作用的分子机制尚不清楚。我们假设，平滑肌细胞骨架动力学稳态是抵御危重血管疾病的关键环节和干预靶标；非编码RNA和IMD通过调节SM22α表达和活性，进而抑制细胞骨架病理性重构、协同抵抗氧化应激、阻断中膜退变和危重血管损伤。本项目通过集成，考查基于细胞骨架稳态的平滑肌抗氧化应激系统与主动脉瘤/夹层发生发展的关系及标志分子的功能验证；揭示非编码RNA和IMD调节SM22α表达和修饰、维持细胞骨架动力学平衡、激活损伤修复的组学特征、信号途径、靶基因和分子机制；阐明以SM22α为核心的血管抗损伤系统的细胞及分子网络；为危重血管疾病的早诊和干预提供新策略

血管平滑肌细胞（VSMC）作为维持血管结构和功能的主要细胞类型，其表型变化是主动脉瘤/夹层形成的关键因素。本项目利用多重组学分析和细胞与分子生物学技术，系统深入研究了在主动脉瘤相关的血管重构过程中，VSMC表型转化的发育轨迹、代谢特征和多维度的调控作用，取得多项重要发现：1）证实VSMC表型转化的发育轨迹是从收缩表型首先转化为合成表型，随之向炎症和成骨样表型逐步演变，提示血管损伤应答是以修复为首要应答方式，阻断其向炎症和成骨样表型转化将是预防主动脉瘤/夹层的关键节点。2）证实敲除平滑肌特异性蛋白SM22α，可导致肠道菌群失衡，拟乳杆菌和保护性代谢产物二甲甘氨酸明显减少，与增加的血管炎症和内膜增厚有关；补充该肠菌或二甲甘氨酸可有效抑制血管炎症和内膜肥厚。结果表明，宿主遗传背景可能是决定肠道菌群稳态和血管稳态的关键因素。3）证实动脉粥样硬化患者和小鼠模型的血浆SM22α水平明显降低；而主动脉夹层及破裂的患者和小鼠模型，其血浆SM22α水平在破裂前和破裂初期明显升高，可用于临床动脉粥样硬化的筛查和主动脉夹层破裂预警，有临床转化前景。4）首次发现并证实，核受体LXRα的核定位受actin动力学调节，胞浆G-actin水平阻滞LXRα的核输入和下游靶基因ABCA1表达，进而导致胆固醇流出障碍。由SM22α所致的actin动力学改变是泡沫细胞形成和动脉粥样硬化的新机制。研究表明，SM22α是维持血管稳态和调节血管重构的关键因子，介导肠道-菌群-血管对话；SM22α缺陷可通过多种途径促发主动脉瘤等危重血管损伤。此外，对miR-126内皮特异性敲除小鼠的单细胞转录组测序发现，miR-126相关细胞亚类与单核细胞趋化和血管钙化密切相关；非编码环RNA circSirt1可抑制NF-κB核转位激活；SIRT1-TgVSMC通过释放外泌体cZFP609，抑制缺氧诱导的内皮细胞HIF-1激活和血管新生；SM22α KO VSMC可招募巨噬细胞，后者通过circRasGEF1B促进VAMC凋亡。血管活性肽IMD通过抑制内质网应激、抑制平滑肌细胞凋亡和抑制巨噬细胞炎症反应进而抑制动脉粥样硬化血管钙化和腹主动脉瘤的发生发展。

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