Ursodeoxycholic acid inhibits intimal hyperplasia, vascular smooth muscle cell excessive proliferation, migration via blocking miR-21/PTEN/AKT/mTOR signaling pathway

Cell Cycle. 2020 Apr;19(8):918-932. doi: 10.1080/15384101.2020.1732514. Epub 2020 Mar 22.

Abstract

Excessive migration and proliferation of vascular smooth muscle cells (VSMCs) are critical cellular events that lead to intimal hyperplasia in atherosclerosis and restenosis. In this study, we investigated the protective effects of ursodeoxycholic acid (UDCA) on intimal hyperplasia and VSMC proliferation and migration, and the underlying mechanisms by which these events occur. A rat unilateral carotid artery was ligated to induce vascular injury and the microRNA (miRNA) expression profiles were determined using miRNA microarray analysis. We observed that UDCA significantly reduced the degree of intimal hyperplasia and induced miR-21 dysregulation. Restoration of miR-21 by agomir-miR-21 reversed the protective effects of UDCA on intimal hyperplasia and proliferation in vivo. In vitro, UDCA suppressed PDGF-BB-induced VSMC proliferation, invasion and migration in a dose-dependent manner, whereas the suppressive effect of UDCA was abrogated by overexpression of miR-21 in PDGF-BB-incubated VSMCs. Furthermore, we identified that miR-21 in VSMCs targeted the phosphatase and tensin homolog (PTEN), a tumor suppressor gene, negatively modulated the AKT/mTOR pathway. More importantly, we observed that that UDCA suppressed AKT/mTOR signaling pathway in the carotid artery injury model, whereas this pathway was reactivated by overexpression of miR-21. Taken together, our findings indicated that UDCA inhibited intimal hyperplasia and VSMCs excessive migration and proliferation via blocking miR-21/PTEN/AKT/mTOR signaling pathway, which suggests that UDCA may be a promising candidate for the therapy of atherosclerosis.

Keywords: Atherosclerosis; intimal hyperplasia; miR-21/PTEN/AKT/mTOR signaling pathway; proliferation; vascular smooth muscle cell.

MeSH terms

  • Animals
  • Antagomirs / administration & dosage
  • Cell Movement / drug effects*
  • Cell Movement / genetics
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Hyperplasia / drug therapy*
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism*
  • Transfection
  • Tunica Intima / drug effects
  • Tunica Intima / pathology*
  • Ursodeoxycholic Acid / administration & dosage*
  • Vascular System Injuries / drug therapy*
  • Vascular System Injuries / metabolism*
  • Vascular System Injuries / pathology

Substances

  • Antagomirs
  • MicroRNAs
  • mirn21 microRNA, rat
  • Ursodeoxycholic Acid
  • mTOR protein, rat
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • Pten protein, rat