Morin inhibits PDGF-induced proliferation, migration, and invasion of vascular smooth muscle cells via modulating p27KIP1, AKT, and MMP-9 activities

Gen Physiol Biophys. 2018 Sep;37(6):633-645. doi: 10.4149/gpb_2018028.

Abstract

Hyper-proliferation and migration of vascular smooth muscle cells (VSMCs) are closely associated with atherosclerosis. Recently, the flavonol morin has been reported to exhibit potent anti-oxidant and anti-inflammatory activities. Therefore, we investigated molecular mechanisms of morin in VSMCs stimulated by PDGF. Morin effectively inhibited PDGF-stimulated proliferation of VSMCs through a G1 cell-cycle arrest, leading to down-regulation of CDK2, CDK4, cyclin D1, and cyclin E proteins. Interestingly, PDGF markedly down-regulated p27KIP1 protein expression; however, morin treatment restored the p27KIP1expression to the basal level. Morin did not affect phosphorylation of MAPKs (ERK, p38, and JNK); however, phosphorylation of AKT was dramatically suppressed by morin in PDGF-stimulated VSMCs. Using the PI3K inhibitor, LY294002, we revealed that AKT is a key regulator in the inhibitory mechanism of morin against PDGF-induced proliferation of VSMCs. Morin disturbed migratory and invasive potential of VSMCs via suppression of matrix metalloproteinase-9 (MMP-9) activity. Using electrophoretic mobility shift assays, we verified that NF-κB, AP-1, and Sp-1 transcription factors are implicated in the mode of action of morin, which suppresses the MMP-9 activity in PDGF-induced VSMCs. Based on the results, we believe that morin may be a potential therapeutic agent for atherosclerosis without negative side effect.

MeSH terms

  • Cell Movement
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p27
  • Flavonoids
  • Matrix Metalloproteinase 9
  • Muscle, Smooth, Vascular
  • Myocytes, Smooth Muscle
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt

Substances

  • Flavonoids
  • Cyclin-Dependent Kinase Inhibitor p27
  • morin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinase 9