MiR-16-5p suppresses myofibroblast activation in systemic sclerosis by inhibiting NOTCH signaling

Aging (Albany NY). 2020 Dec 19;13(2):2640-2654. doi: 10.18632/aging.202308. Epub 2020 Dec 19.

Abstract

Systemic sclerosis (SSc) is a prototypic fibrotic disease characterized by localized or diffuse skin thickening and fibrosis. Tissue fibrosis is driven by myofibroblasts, and factors affecting myofibroblast activation may also be involved in the development of SSc. In this study, we examined molecular mechanisms underlying SSc by focusing on myofibroblast activation processes. Bioinformatics analysis conducted to identify differentially expressed miRNAs (DEMs) and genes (DEGs) revealed that microRNA-16-5p (miR-16-5p) was downregulated and NOTCH2 was upregulated in SSc patients. In vitro experiments confirmed that miR-16-5p was able to bind directly to NOTCH2 and inhibit myofibroblast activation. Moreover, miR-16-5p-dependent inhibition of NOTCH2 decreased collagen and α-SMA expression. MiR-16-5p downregulation and NOTCH2 upregulation was also confirmed in vivo in SSc patients, and NOTCH2 activation promoted fibrosis progression in vitro. These results indicate that miR-16-5p suppresses myofibroblast activation by suppressing NOTCH signaling.

Keywords: NOTCH; SSc; miRNA; myofibroblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Case-Control Studies
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Down-Regulation
  • Humans
  • In Vitro Techniques
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 8 / genetics
  • Matrix Metalloproteinase 8 / metabolism
  • MicroRNAs / agonists
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Myofibroblasts / metabolism*
  • RNA, Messenger / metabolism*
  • RNA, Small Interfering
  • Receptor, Notch2 / genetics*
  • Receptor, Notch2 / metabolism
  • Scleroderma, Systemic / genetics*
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Signal Transduction
  • Up-Regulation

Substances

  • ACTA2 protein, human
  • Actins
  • CCN2 protein, human
  • COL1A2 protein, human
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • MIRN16 microRNA, human
  • MicroRNAs
  • NOTCH2 protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptor, Notch2
  • Connective Tissue Growth Factor
  • MMP8 protein, human
  • Matrix Metalloproteinase 8
  • MMP1 protein, human
  • Matrix Metalloproteinase 1