长链非编码 RNA TUG1 通过海绵吸附 miR-204-5p 而上调 Runx2 促进主动脉瓣钙化中的成骨细胞分化。

LncRNA TUG1 sponges miR-204-5p to promote osteoblast differentiation through upregulating Runx2 in aortic valve calcification.

机构信息

Department of Vascular Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310003, Zhejiang Province, China.

Department of Cardiovascular Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.

出版信息

Cardiovasc Res. 2018 Jan 1;114(1):168-179. doi: 10.1093/cvr/cvx180.

DOI:10.1093/cvr/cvx180

PMID:29016735

Abstract

AIMS

Emerging evidence indicates that long non-coding RNAs (lncRNAs) play a vital role in cardiovascular physiology and pathology. Although the lncRNA TUG1 is implicated in atherosclerosis, its function in calcific aortic valve disease (CAVD) remains unknown.

METHODS AND RESULTS

In this study, we found that TUG1 was highly expressed in human aortic valves and primary valve interstitial cells (VICs). Moreover, TUG1 knockdown induced inhibition of osteoblast differentiation in CAVD both in vitro and in vivo. Mechanistically, silencing of TUG1 increased the expression of miR-204-5p and subsequently inhibited Runx2 expression at the post-transcriptional level. Importantly, TUG1 directly interacted with miR-204-5p and downregulation of miR-204-5p efficiently reversed the suppression of Runx2 induced by TUG1 short hairpin RNA (shRNA). Thus, TUG1 positively regulated the expression of Runx2, through sponging miR-204-5p, and promoted osteogenic differentiation in CAVD.

CONCLUSION

All together, the evidence generated by our study elucidates the role of lncRNA TUG1 as a miRNA sponge in CAVD, and sheds new light on lncRNA-directed diagnostics and therapeutics in CAVD.

摘要

目的

越来越多的证据表明，长非编码 RNA（lncRNA）在心血管生理学和病理学中起着至关重要的作用。尽管 lncRNA TUG1 与动脉粥样硬化有关，但它在心脏瓣膜钙化（CAVD）中的作用尚不清楚。

方法和结果

在这项研究中，我们发现 TUG1 在人主动脉瓣和原代心脏瓣膜间质细胞（VIC）中高表达。此外，TUG1 敲低可在体外和体内均抑制 CAVD 中的成骨细胞分化。机制上，沉默 TUG1 可增加 miR-204-5p 的表达，进而在转录后水平抑制 Runx2 的表达。重要的是，TUG1 可直接与 miR-204-5p 相互作用，而下调 miR-204-5p 可有效逆转 TUG1 短发夹 RNA（shRNA）对 Runx2 的抑制作用。因此，TUG1 通过海绵吸附 miR-204-5p 正向调节 Runx2 的表达，促进 CAVD 中的成骨细胞分化。