MCPIP3选择性调控血管内皮炎症在腹主动脉瘤发病中的作用及其机制研究

项目名称： MCPIP3选择性调控血管内皮炎症在腹主动脉瘤发病中的作用及其机制研究

项目编号： No.81470577

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘玲

作者单位： 中南大学

项目金额： 75万元

中文摘要： 腹主动脉瘤（AAA）病死率居高不下，为其探讨新的治疗策略是目前大血管疾病领域的研究热点。NF-κB 信号通路介导的血管内皮炎症是触发AAA发病过程中血管中层和外膜炎症反应的早期信号，选择性阻断内皮NF-κB 信号通路可抑制AAA形成。申请人近期发现AAA急性破裂患者病灶中的巨噬细胞趋化蛋白诱导的蛋白3（MCPIP3）基因表达高于正常主动脉，而且在国际上首次报导MCPIP3过表达有效抑制NF-κB 信号通路介导的血管内皮炎症。故推测：新型抗炎因子MCPIP3可能通过特异性抑制血管内皮NF-κB 信号通路来减轻血管炎症、抑制AAA的形成。申请人拟建立血管内皮细胞特异表达人MCPIP3的ApoE-/-转基因小鼠，在分子、细胞、动物的水平上，综合性地研究血管内皮细胞特异性表达人MCPIP3对血管紧张素II诱导的ApoE-/-小鼠腹主动脉瘤形成的调控作用及其机制。以期为临床防治AAA开拓新的思路。

中文关键词： 腹主动脉瘤；血管重构；动脉粥样硬化

英文摘要： Abdominal aortic aneurysm (AAA) is a common vascular condition with life-threatening implications from aortic rapture, which has a motality rate as high as 90%. Surgical repair by standard means or interventional endovascular stent placement is the only option for treatment. Currently, there are no available nonsurgical therapies to treat AAA. Therefore, devoloping pharmacological prevention strategies to block AAA progression is a high priority. Recently, a study showed that endothelial NF-κB activation colud trigger macrophage-induced inflammation in the adventitia and media during the formation of AAA through up-regulating adhesion molecule expression. Additionally, the blockade of endothelial NF-κB signaling pathway prevented AAA formation in an experimental model, hypercholesterolaemic apolipoprotein E-deficient (ApoE-/-) mice with angiotensin II infuson. The applicant found that mRNA expression of a novel anti-inflammatory factor, monocyte chemoa-tracttant protein-induced protein 3(MCPIP3), increased in the endothelium of aneurysmal aorta but not in that of normal aorta in patients with ruptured AAA, and firstly demonstrated that MCPIP3 inhibited tumor necrosis factor α-induced expressions of chemokins and adhesion molecules, and thus reduced THP-1 monocyte adherence to endothelial cells by repressing NF-κB activation. Moreover, overexpression of MCPIP3 gene reduced expression of monocyte chemoa-tracttant protein 1, which is critical for AAA formation, induced by angiotensin II in human umbilical veins endothelial cells. It is reasonable to conjecture that MCPIP3 may inhibit vascular inflammation and the formation of AAA through selectively inhibiting endothelial NF-κB signaling pathway. The applicant would generate ApoE-/- mice expressing human MCPIP3 selectively in endothelial cells, and explore the potential role and mechanism of human MCPIP3 selective expression in endothelial cell in the formation of AAA. The present study is helpful to explore and enrich the pathogenic mechanism of AAA, and the result of this study is expected to begin a new train of thought for preventing and treating AAA.

英文关键词： abdominal aortic aneurysm;vascular remodling;atherosclerosis