Anti-receptor for advanced glycation end products therapies as novel treatment for abdominal aortic aneurysm.
Anti-receptor for advanced glycation end products therapies as novel treatment for abdominal aortic aneurysm.
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DOI：
10.1097/sla.0b013e3181b41a18
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发表时间：
2009-09
影响因子：
9
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Zhang F;Kent KC;Yamanouchi D;Zhang Y;Kato K;Tsai S;Nowygrod R;Schmidt AM;Liu B
腹主动脉瘤（AAA）破裂是一种破坏性事件，通过抑制小动脉瘤生长的治疗可能可以预防。晚期糖基化终末产物受体（Receptor of advanced glycation end products，RECEPTOR）参与了包括动脉粥样硬化和阿尔茨海默病在内的年龄相关疾病的发生。因此，我们探讨了是否也可能有助于AAAs的形成。我们发现，与正常主动脉组织相比，在人类动脉瘤标本中，VEGF及其配体AGE的表达高度升高，这暗示了VEGF在AAA中的作用。在AAA的小鼠模型中，AAA基因缺失（敲除）显著地将AAA的发病率降低至对照的1/3（对照中75.0%的AAA对敲除25.0%的AAA）。此外，主动脉直径显着减少，在基因敲除动物与对照组。至于机制，我们发现在AAA巨噬细胞中，MMP-9与MMP-9共表达，MMP-9是基质降解的促进剂，已知其诱导AAA。在体外，晚期糖基化终末产物（AGE）诱导MMP-9的产生在巨噬细胞中以剂量依赖性的方式，而阻断与可溶性AGE抑制剂阻止MMP-9的表达。在体内，MMP-9基因缺陷消除了MMP-9活性，这是普遍存在于野生型小鼠的血管壁。黄芪可通过诱导MMP-9的表达促进AAA的发生发展。在小鼠动脉瘤模型中阻断血管紧张素Ⅱ对动脉瘤的形成具有显著的抑制作用。这些数据表明，应该设计更大的动物试验和最终的人体试验来测试口服抗动脉瘤药及其预防小动脉瘤进展的潜力。
Rupture of abdominal aortic aneurysms (AAA) is a devastating event potentially preventable by therapies that inhibit growth of small aneurysms. Receptor of advanced glycation end products (RAGE) has been implicated in age related diseases including atherosclerosis and Alzheimer’s. Consequently, we explored whether RAGE may also contribute to the formation of AAAs. Implicating a role for RAGE in AAA, we found the expression of RAGE and its ligand AGE were highly elevated in human aneurysm specimens as compared to normal aortic tissue. In a mouse model of AAA, RAGE gene deletion (knockout) dramatically reduced the incidence of AAA to 1/3 of control (AAAs in 75.0% of controls versus 25.0% knockouts). Moreover, aortic diameter was markedly reduced in RAGE knockout animals versus controls. As to mechanism, we found that RAGE was co-expressed in AAA macrophages with MMP-9, a promoter of matrix degradation, which is known to induce AAA. In vitro, advanced glycation end products (AGE) induced the production of MMP-9 in macrophages in a dose-dependent manner while blocking RAGE signaling with a soluble AGE inhibitor prevented MMP-9 expression. In vivo, RAGE gene deficiency eliminated MMP-9 activity that was prevalent in aneurismal wall of the wild-type mice. RAGE promotes the development of AAA by inducing MMP-9 expression. Blocking RAGE in a mouse aneurysm model has a dramatic inhibitory effect on the formation of aneurysms. These data suggest that larger animal and eventually human trials should be designed to test oral RAGE inhibitors and their potential to prevent progression of small aneurysms.