Small size apolipoprotein(a) isoforms enhance inflammatory and proteolytic potential of collagen-primed monocytes

Lipids Health Dis. 2019 Aug 31;18(1):166. doi: 10.1186/s12944-019-1106-4.

Abstract

Background: Atherosclerosis is an inflammatory process involving activation of monocytes recruited by various chemoattractant factors, among which lipoprotein(a) and its specific apolipoprotein apo(a). Lp(a) contains a specific apolipoprotein apo(a) which size is determined by a variable number of repeats of a specific structural domain, the kringle IV type 2 (IV-2). Lp(a) plasma concentration and apo(a) size is inversely correlated, and smaller apo(a) are major risk factors for coronary heart disease.

Design and methods: The aim of this study was to evaluate the effect of recombinant apo(a) isoforms (containing 10, 18 or 34 kringles) on monocytes interacting with type I collagen.

Results: Apo(a) isoforms stimulated reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) production by monocytes, and not modified monocytes adhesion on type I collagen. This effect was specific of apo(a) since no effect was observed in the presence of plasminogen and was inversely related to apo(a) size. The lysine analogue 6-aminohexanoic acid which blocks the lysine binding sites (LBS), and carboxypeptidase B (CpB) which cleaves carboxy-terminal lysine residues, abolished apo(a)-induced ROS and MMP-9 production, highlighting an effect mediated by apo(a) lysing-binding sites.

Conclusions: These results indicate that activation of collagen-primed monocytes stimulated with apo(a) is a Kringle number-dependent effect and reinforce the hypothesis of a role for small size apo(a) isoforms in atherothrombosis.

Keywords: Apolipoprotein(a); Atherosclerosis; Collagen; Lipoprotein(a); Monocytes.

MeSH terms

  • Aminocaproic Acid / pharmacology
  • Animals
  • Apolipoproteins A / biosynthesis
  • Apolipoproteins A / chemistry
  • Apolipoproteins A / pharmacology*
  • Collagen Type I / pharmacology*
  • Fibronectins / pharmacology
  • HEK293 Cells
  • Humans
  • Matrix Metalloproteinase 9 / biosynthesis
  • Molecular Weight
  • Monocytes / cytology
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Plasminogen / pharmacology
  • Primary Cell Culture
  • Protein Binding
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / chemistry
  • Protein Isoforms / pharmacology
  • Proteolysis
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / pharmacology*

Substances

  • Apolipoproteins A
  • Collagen Type I
  • Fibronectins
  • Protein Isoforms
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Plasminogen
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • Aminocaproic Acid