Osteoglycin在主动脉瘤发生发展中的作用和机制研究

Aortic aneurysm is a multifactorial aortic disease with a potential risk of rupture. Once the aneurysm ruptures, its mortality rate is extremely high. Therefore, it is very important to explore the pathological mechanism of aortic aneurysm, as well as early prevention and intervention. Osteoglycin (OGN), a member of the small leucine rich protein (SLRP) family, is involved in the synthesis of extracellular matrix and regulation of collagen fibers. The expression of OGN in human aneurysm tissues was significantly down-regulated from reported microarray analysis and proteomic study, suggesting that OGN may be involved in the occurrence and development of aneurysms. Our preliminary experiments showed that aortic aneurysm or dissection (AAD) was induced following 2-week angiotensin II (Ang II) infusion in OGN knockout (KO) mice, with a total incidence of 60%, whereas none of the wild-type control mice can develop aneurysm or dissection. Hence, it raised our interest to explore the reason why OGN KO mice can develop AAD and the underlying molecular mechanism. In this study, we aimed to find out the effect of OGN loss on vascular wall structure, elastic fiber fracture, matrix metalloproteinase activity, and to investigate the interaction between OGN and its target proteins, as well as related intracellular signaling pathways. Therefore, with the deepening of the research, the mechanism of OGN in maintaining the stability of vascular wall structure and preventing the occurrence of AAD will be gradually elucidated, providing a scientific theoretical basis for the clinical prevention and treatment of aortic aneurysms and dissections.

主动脉瘤是一种多致病因子的主动脉病理扩张性疾病，具有潜在破裂风险，致死率极高，因此，从预防着手，寻找动脉瘤相关致病基因，减轻动脉瘤性疾病的发生进展，对改善疾病的预后具有重要的意义。Osteoglycin（OGN）是小亮氨酸富集蛋白家族成员，参与细胞外基质的合成及胶原纤维的调控。本课题组前期研究发现，OGN基因敲除小鼠在血管紧张素II灌注诱导的高血压模型中可致主动脉瘤样扩张、主动脉夹层甚至破裂死亡，而野生型对照组小鼠事件发生率为零。基于此，本课题组将进一步研究：1）对比观察OGN基因敲除组与对照组小鼠在血管形态、弹力层结构、胶原纤维和基质金属蛋白酶水平等病理生理学差异。2）寻找OGN的作用靶点，阐明其通过介导何种信号通路的改变以维持血管结构的稳定性。随着课题研究不断深入，OGN在维持血管壁结构稳定并防止动脉瘤及夹层发生的作用机制将逐步被阐明，为主动脉瘤及夹层的临床防治提供科学依据。

主动脉瘤是一种多致病因子的主动脉病理扩张性疾病，具有潜在破裂风险，致死率极高，因此，从预防着手，寻找动脉瘤相关致病基因，减轻动脉瘤性疾病的发生进展，对改善疾病的预后具有重要的意义。Osteoglycin（OGN）是小亮氨酸富集蛋白家族成员，参与细胞外基质的合成及胶原纤维的调控。在体实验提示OGN基因敲除小鼠在血管紧张素II灌注诱导的高血压模型中可致主动脉瘤样扩张、主动脉夹层甚至破裂死亡，而野生型对照组小鼠事件发生率为零。组织形态学及免疫组化检查显示OGN基因敲除小鼠血管组织中OGN敲除组血管壁弹力纤维断裂，血管壁代偿性纤维化，局部组织炎症细胞大量聚集，胶原纤维显著增多；电镜结果显示OGN基因敲除组胶原纤维管壁直径粗细不一，影响了整个血管壁抗牵张能力。功能回补实验显示，上调敲除小鼠体内OGN基因的表达，可以将主动脉瘤模型小鼠的主动脉瘤及夹层发生率下降至20%。与体内实验结果一致的，调控血管平滑肌细胞内OGN的表达，可以显著影响血管平滑肌细胞增殖、迁移以及合成胶原的能力，另外，敲低细胞内OGN的表达，可以显著增强细胞MMP2/MMP9的活性。机制上，我们发现VEGF/VEFGR-AKT/ERK1/2通路是OGN在主动脉瘤/夹层病理过程中发挥作用的潜在机制。