Deletion of the FHL2 gene attenuates intima-media thickening in a partially ligated carotid artery ligated mouse model

J Cell Mol Med. 2020 Jan;24(1):160-173. doi: 10.1111/jcmm.14687. Epub 2019 Nov 12.

Abstract

The four and a half LIM domain protein 2 (FHL2) is a member of the four and a half LIM domain (FHL) gene family, and it is associated with cholesterol-enriched diet-promoted atherosclerosis. However, the effect of FHL2 protein on vascular remodelling in response to hemodynamic alterations remains unclear. Here, we investigated the role of FHL2 in a model of restricted blood flow-induced atherosclerosis. To promote neointimal hyperplasia in vivo, we subjected FHL2+/+ and FHL2-/- mice to partial ligation of the left carotid artery (LCA). The expression of p-ERK and p-AKT was decreased in FHL2-/- mice. FHL2 bound to AKT regulated AKT phosphorylation and led to Rac1-GTP inactivation. FHL2 silencing in human aortic smooth muscle cells down-regulated the PDGF-induced phosphorylation of ERK and AKT. Furthermore, FHL2 silencing reduced cytoskeleton conformational changes and caused cell cycle arrest. We concluded that FHL2 is essential for the regulation of arterial smooth muscle cell function. FHL2 modulates proliferation and migration via mitogen-activated protein kinase (MAPK) and PI3K-AKT signalling, leading to arterial wall thickening and thus neointimal hyperplasia.

Keywords: FHL2; carotid artery ligation; neointimal hyperplasia; smooth muscle cell.

MeSH terms

  • Animals
  • Atherosclerosis / etiology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Carotid Arteries / pathology*
  • Carotid Arteries / surgery
  • Carotid Intima-Media Thickness*
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Gene Deletion*
  • LIM-Homeodomain Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Proteins / physiology*
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Signal Transduction
  • Transcription Factors / physiology*

Substances

  • Fhl2 protein, mouse
  • LIM-Homeodomain Proteins
  • Muscle Proteins
  • Transcription Factors