Clearance of matrix metalloproteinase-9 is dependent on low-density lipoprotein receptor-related protein-1 expression downregulated by microRNA-205 in human abdominal aortic aneurysm
Clearance of matrix metalloproteinase-9 is dependent on low-density lipoprotein receptor-related protein-1 expression downregulated by microRNA-205 in human abdominal aortic aneurysm
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DOI：
10.1016/j.jvs.2015.10.065
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发表时间：
2017-02-01
影响因子：
4.3
通讯作者：
Cheng, Stephen Wing Keung
中科院分区：
文献类型：
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作者：
Chan, Crystal Yin Tung;Chan, Yiu Che;Cheng, Stephen Wing Keung
目的：低密度脂蛋白受体相关蛋白-1（LRP 1）在腹主动脉瘤（AAA）的发病机制中起着重要的调节作用。我们之前使用人类主动脉样本的研究进一步揭示了与AAA相关的LRP 1蛋白表达的显着减少。然而，LRP 1在AAA病理生理学中的下调仍未解决。我们假设LRP 1下调可能是由microRNA（miR）介导的，并且LRP 1可能作为基质金属蛋白酶-9（MMP-9）的清除剂发挥作用，MMP-9是一种众所周知的蛋白酶，用于降解AAA发病机制中主动脉壁的细胞外基质蛋白。本研究探讨了LRP 1下调的原因及其在AAA发病机制中的潜在作用。LRP 1蛋白、LRP 1信使RNA（mRNA）及其三种预测的miR候选物的观察性研究（miR-205、miR-338- 5 p和miR-545- 3 p）首次在AAA中与来自人类的非囊性组织进行比较，随后进行功能研究，测试在从人腹主动脉组织培养的人血管平滑肌细胞（VSMC）外植体中miR-205过表达和敲低对LRP 1表达的影响。最后，进行了另一项功能研究，以测试在人VSMC中沉默LRP 1后外源性MMP-9的清除。
Objective: Low-density lipoprotein receptor-related protein-1 (LRP1) has been suggested to be a crucial regulator in the pathogenesis of abdominal aortic aneurysm (AAA) from previous genome association and animal studies. Our prior study using human aortic samples has further revealed a significant reduction of LRP1 protein expression associated with AAA. However, the downregulation of LRP1 in the pathophysiology of AAA remained unresolved. We hypothesized that LRP1 downregulation may be mediated by microRNA (miR) and that LRP1 may function as a scavenger of matrix metalloproteinase-9 (MMP-9), a well-known protease for degradation of extracellular matrix proteins at the aortic wall for AAA pathogenesis. This study investigated the cause of LRP1 downregulation and its potential effect on AAA pathogenesis.Methods: An observational study of LRP1 protein, LRP1 messenger RNA (mRNA), and its three predicted miR candidates (miR-205, miR-338-5p, and miR-545-3p) was first performed in AAA compared with nonaneurysmal tissues from humans, followed by a functional study testing the effect on LRP1 expression of miR-205 overexpression and knockdown in human vascular smooth muscle cells (VSMCs) explant cultured from human abdominal aortic tissues. Lastly, another functional study was performed to test for the clearance of exogenous MMP-9 upon silencing of LRP1 in human VSMCs.Results: From the observational study, significantly higher miR-205 (P