Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model

Atherosclerosis. 2018 Jul:274:120-127. doi: 10.1016/j.atherosclerosis.2018.05.008. Epub 2018 May 5.

Abstract

Background and aims: Proteoglycan 4 (Prg4) has a high structural similarity with the established atherosclerosis-modulating proteoglycan versican, but its role in atherogenesis is still unknown. Therefore, the impact of Prg4 deficiency on macrophage function in vitro and atherosclerosis susceptibility in vivo was investigated.

Methods: The presence and localization of Prg4 was studied in atherosclerotic lesions. Furthermore, the effect of Prg4 deficiency on macrophage foam cell formation, cholesterol efflux and lipopolysaccharide (LPS) response was determined. Finally, susceptibility for atherosclerotic lesion formation was investigated in bone marrow-specific Prg4 knockout (KO) mice.

Results: Prg4 mRNA expression was induced 91-fold (p<0.001) in murine initial atherosclerotic lesions and Prg4 protein co-localized with human lesional macrophages. Murine Prg4 KO macrophages showed increased foam cell formation (+2.1-fold, p<0.01). In parallel, the expression of the cholesterol efflux genes ATP-binding cassette transporter A1 and scavenger receptor type B1 was lower (-35%, p<0.05;-40%, p<0.05) in Prg4 KO macrophages. This translated into an impaired cholesterol efflux to high-density lipoprotein (-13%, p<0.001) and apolipoprotein A1 (-8%, p<0.05). Furthermore, Prg4 KO macrophages showed an impaired LPS-induced rise in TNFα secretion as compared to wild-type controls (-31%, p<0.001), indicating a reduced inflammatory response. Combined, these pro- and anti-atherogenic effects did not translate into a significant difference in atherosclerotic lesion formation upon bone marrow-specific deletion of Prg4 in low-density lipoprotein receptor KO mice.

Conclusions: Prg4 is present in macrophages in both murine and human atherosclerotic lesions and critically influences macrophage function, but deletion of Prg4 in bone marrow-derived cells does not affect atherosclerotic lesion development.

Keywords: Atherosclerosis; Bone marrow transplantation; Macrophage function; Proteoglycan 4; Proteoglycans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Cells / pathology
  • Bone Marrow Transplantation
  • Carotid Arteries / metabolism*
  • Carotid Arteries / pathology
  • Carotid Artery Diseases / genetics
  • Carotid Artery Diseases / metabolism*
  • Carotid Artery Diseases / pathology
  • Cells, Cultured
  • Cholesterol / metabolism
  • Disease Models, Animal
  • Foam Cells / drug effects
  • Foam Cells / metabolism*
  • Foam Cells / pathology
  • Foam Cells / transplantation
  • Humans
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism*
  • Macrophages, Peritoneal / pathology
  • Macrophages, Peritoneal / transplantation
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Phenotype
  • Plaque, Atherosclerotic*
  • Proteoglycans / deficiency
  • Proteoglycans / genetics
  • Proteoglycans / metabolism*
  • Scavenger Receptors, Class B / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • ABCA1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • Inflammation Mediators
  • Lipopolysaccharides
  • PRG4 protein, human
  • Prg4 protein, mouse
  • Proteoglycans
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • Tumor Necrosis Factor-alpha
  • Cholesterol