Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening

Cell Rep. 2012 Nov 29;2(5):1259-71. doi: 10.1016/j.celrep.2012.09.018. Epub 2012 Oct 25.

Abstract

Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple is unknown. Here, we show that apolipoprotein E (apoE) and apoE-containing high-density lipoprotein (apoE-HDL) maintain arterial elasticity by suppressing the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop that increases the expression of collagen-I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain and transduced by Cox2 and miR-145. Arterial stiffness is increased in apoE null mice. This stiffening can be reduced by administration of the lysyl oxidase inhibitor BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. We conclude that apoE and apoE-containing HDL promote healthy arterial biomechanics and that this confers protection from cardiovascular disease independent of the established apoE-HDL effect on cholesterol.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminopropionitrile / pharmacology
  • Aminopropionitrile / therapeutic use
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Apolipoprotein E3 / pharmacology
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Atherosclerosis / drug therapy
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Cells, Cultured
  • Cholesterol, HDL / pharmacology*
  • Collagen Type I / metabolism
  • Cyclooxygenase 2 / metabolism
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Fibronectins / metabolism
  • Gene Expression
  • Humans
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / metabolism
  • Protein-Lysine 6-Oxidase / antagonists & inhibitors
  • Protein-Lysine 6-Oxidase / genetics
  • Protein-Lysine 6-Oxidase / metabolism
  • Vascular Stiffness / drug effects

Substances

  • Apolipoprotein E3
  • Apolipoproteins E
  • Cholesterol, HDL
  • Collagen Type I
  • Extracellular Matrix Proteins
  • Fibronectins
  • MIRN145 microRNA, mouse
  • MicroRNAs
  • Lox protein, mouse
  • Aminopropionitrile
  • Cyclooxygenase 2
  • Protein-Lysine 6-Oxidase

Associated data

  • GEO/GSE40637