Lethal giant larvae 1 inhibits smooth muscle calcification via high mobility group box 1

J Mol Cell Cardiol. 2020 May:142:39-52. doi: 10.1016/j.yjmcc.2020.03.017. Epub 2020 Apr 5.

Abstract

Vascular calcification is a pathological process closely related to atherosclerosis, diabetic vascular diseases, vascular injury, hypertension, chronic kidney disease and aging. Lethal giant larvae 1 (LGL1) is known as a key regulator of cell polarity and plays an important role in tumorigenesis. However, whether LGL1 regulates vascular calcification remains unclear. In this study, we generated smooth muscle-specific LGL1 knockout (LGL1SMKO) mice by cross-breeding LGL1flox/flox mice with α-SMA-Cre mice. LGL1 level was significantly decreased during calcifying conditions. Overexpression of LGL1 restrained high phosphate-induced calcification in vascular smooth muscle cells (VSMCs). Mechanically, LGL1 could bind with high mobility group box 1 (HMGB1) and promote its degradation via the lysosomal pathway, thereby inhibiting calcification. Smooth muscle-specific deletion of LGL1 increased HMGB1 level and aggravated vitamin D3-induced vascular calcification, which was attenuated by an HMGB1 inhibitor. LGL1 may inhibit vascular calcification by preventing osteogenic differentiation via promoting HMGB1 degradation.

Keywords: HMGB1; LGL1; Osteogenic differentiation; Runx2; Vascular calcification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / etiology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Biomarkers
  • Calcinosis / etiology*
  • Calcinosis / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression
  • Glycoproteins / deficiency
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • HMGB1 Protein / genetics*
  • HMGB1 Protein / metabolism
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology*
  • Myocytes, Smooth Muscle / metabolism
  • Protein Binding
  • Vitamin D / metabolism

Substances

  • Biomarkers
  • Glycoproteins
  • HMGB1 Protein
  • LGL1 protein, mouse
  • Vitamin D