Broad-spectrum chemokine inhibition reduces vascular macrophage accumulation and collagenolysis consistent with plaque stabilization in mice

J Vasc Res. Nov-Dec 2005;42(6):492-502. doi: 10.1159/000088139. Epub 2005 Sep 7.

Abstract

Background: A major determinant of the risk of myocardial infarction is the stability of the atherosclerotic plaque. Macrophage-rich plaques are more vulnerable to rupture, since macrophages excrete an excess of matrix-degrading enzymes over their inhibitors, reducing collagen content and thinning the fibrous cap. Several genetic studies have shown that disruption of signalling by the chemokine monocyte chemoattractant protein 1 reduced the lipid lesion area and macrophage accumulation in the vessel wall.

Methods: We have tested whether a similar reduction in macrophage accumulation could be achieved pharmacologically by treating apolipoprotein-E-deficient mice with the chemokine inhibitor NR58-3.14.3.

Results: Mice treated for various periods of time (from several days to 6 months) with NR58-3.14.3 (approximately 30 mg/kg/day) consistently had 30-40% fewer macrophages in vascular lesions, compared with mice treated with the inactive control NR58-3.14.4 or PBS vehicle. Similarly, cleaved collagen staining was lower in mice treated for up to 7 days, although this effect was not maintained when treatment time was extended to 12 weeks. The vascular lipid lesion area was unaffected by treatment, but total collagen I staining and smooth muscle cell number were both increased, suggesting that a shift to a more stable plaque phenotype had been achieved.

Conclusions: Strategies, such as chemokine inhibition, to attenuate macrophage accumulation may therefore be useful to promote stabilization of atherosclerotic plaques.

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Aorta / pathology*
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • CD11b Antigen / metabolism
  • Chemokines / antagonists & inhibitors*
  • Collagen / chemistry
  • Collagen / metabolism*
  • Immunohistochemistry / methods
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / pathology
  • Peptides, Cyclic / pharmacokinetics
  • Peptides, Cyclic / pharmacology
  • Staining and Labeling

Substances

  • Apolipoproteins E
  • CD11b Antigen
  • Chemokines
  • Peptides, Cyclic
  • cyclo(cysteinyl-glutaminyl-isoleucyl-tryptophyl-lysyl-glutaminyl-lysyl-prolyl-aspartyl-leucyl-cysteinyl-amide)
  • Collagen