Upregulation of a disintegrin and metalloproteinase with thrombospondin motifs-7 by miR-29 repression mediates vascular smooth muscle calcification

Yaoyao Du, Cheng Gao, Ziyi Liu, Li Wang, Bo Liu, Fan He, Tao Zhang, Yue Wang, Xiujie Wang, Mingjiang Xu, Guan Zheng Luo, Yi Zhu, Qingbo Xu, Xian Wang, Wei Kong

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

Objective.Vascular calcification significantly increases cardiovascular morbidity and mortality. We recently reported that the deficiency of cartilage oligomeric matrix protein (COMP) leads to vascular mineralization. We characterized the COMP-degrading metalloproteinase, a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7). Here, we tested whether ADAMTS-7 facilitates vascular calcification. Methods and Results.ADAMTS-7 expression was markedly upregulated in calcifying rat vascular smooth muscle cells (VSMCs) in vitro, calcified arteries of rats with chronic renal failure in vivo, and radial arteries of uraemic patients. Silencing of ADAMTS-7 markedly reduced COMP degradation and ameliorated VSMC calcification, whereas ectopic expression of ADAMTS-7 greatly enhanced COMP degradation and exacerbated mineralization. The transcriptional activity of ADAMTS-7 promoter was not altered by high phosphate. We used bioinformatics and quantitative polymerase chain reaction analysis to demonstrate that high-phosphate upregulated ADAMTS-7 mRNA and protein via miR-29a/b repression, which directly targeted the 3' untranslated region of ADAMTS-7 in VSMCs. MicroRNA (MiR)-29a/b mimic markedly inhibited but miR-29a/b inhibitor greatly enhanced high-phosphate.induced ADAMTS-7 expression, COMP degradation, and subsequent VSMC calcification. ADAMTS-7 silencing significantly diminished miR-29a/b repression.exaggerated VSMC calcification. Conclusion.Our data reveal a novel mechanism by which ADAMTS-7 upregulation by miR-29a/b repression mediates vascular calcification, which may shed light on preventing cardiovascular morbidity and mortality.

Original languageEnglish
Pages (from-to)2580-2588
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number11
DOIs
StatePublished - Nov 2012
Externally publishedYes

Keywords

  • Animal model of human disease remodeling
  • Calcification
  • MicroRNA
  • Protease
  • Smooth muscle cell

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