The Angiogenic Effect of microRNA-21 Targeting TIMP3 through the Regulation of MMP2 and MMP9

被引：68
作者：
Hu, Jianzhong [1 ]
Ni, Shuangfei [1 ]
Cao, Yong [1 ]
Zhang, Tao [1 ]
Wu, Tianding [1 ]
Yin, Xianzhen [2 ]
Lang, Ye [1 ]
Lu, Hongbin [3 ]
机构：
[1] Cent S Univ, Xiangya Hosp, Dept Spine Surg, Changsha 410008, Hunan, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Delivery Syst, Shanghai 201203, Peoples R China
[3] Cent S Univ, Xiangya Hosp, Res Ctr Sports Med, Dept Sports Med, Changsha 410008, Hunan, Peoples R China
来源：
PLOS ONE | 2016年 / 11卷 / 02期
基金：
中国国家自然科学基金;
关键词：
SPINAL-CORD-INJURY; TISSUE INHIBITOR; MATRIX METALLOPROTEINASES; IN-VITRO; CONTUSION INJURY; DOWN-REGULATION; TUMOR-GROWTH; MIR-21; APOPTOSIS; EXPRESSION;
D O I：
10.1371/journal.pone.0149537
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
microRNAs are a novel set of small, non-protein-coding nucleotide RNAs that negatively regulate the expression of target mRNAs. miRNA-21 is a microRNA that is highly enriched in endothelial cells. miRNA-21 has been shown to be a potential pro-angiogenic factor in some biological systems. Our previous study showed that the expression of miRNA-21 was up-regulated after spinal cord injury. However, the effect of miRNA-21 on angiogenesis in the spinal cord was unclear. In this study, to understand the role of miRNA-21 on injured endothelial cells exclusively, an oxygen and glucose deprivation model of endothelial cells was constructed, and the up-regulation of miRNA-21 was discovered in this model. An increased level of miRNA-21 by mimics promoted the survival, migration and tube formation of endothelial cells, which simultaneously inhibited tissue inhibitor of metalloproteinase-3 (TIMP3) expression and promoted matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) expression and secretion. A decreased level of miRNA-21 by antagomir exerted an opposite effect. As is well known, survival, migration and tube formation of endothelial cells are necessary prerequisites for angiogenesis after injury. TIMP3 was validated as a direct target of miRNA-21 by dual-luciferase reporter assay. Silencing with small interfering RNA against TIMP3 promoted tube formation and increased MMP2 and MMP9 expression at the protein level. In vivo, we found that decreased levels of miRNA-21 inhibited angiogenesis after spinal cord injury in rats using synchrotron radiation micro-computed tomography. In summary, these findings suggest that miRNA-21 has a protective effect on angiogenesis by reducing cell death and promoting cell survival, migration and tube formation via partially targeting the TIMP3 by potentially regulating MMP2 and MMP9. TIMP3 is a functional target gene. Identifying the role of miRNA-21 in the protection of angiogenesis might offer a novel therapeutic target for secondary spinal cord injury, in which angiogenesis is indispensable.
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页数：20
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