en
Scientific article
English

A novel RANTES antagonist prevents progression of established atherosclerotic lesions in mice

Published inArteriosclerosis, thrombosis, and vascular biology, vol. 28, no. 6, p. 1090-1096
Publication date2008
Abstract

BACKGROUND: Atherosclerosis is a chronic inflammatory disease that represents the primary cause of death through coronary disease and stroke. Chemokines are known to play a crucial role in this disease by recruiting inflammatory leukocytes to the endothelium. Recently, the chemokine variant [44AANA47]-RANTES was shown to impair inflammatory cell recruitment in vivo by interfering with heparin binding and oligomerization. METHODS AND RESULTS: In this study we report that curative treatment with [44AANA47]-RANTES limits atherosclerotic plaque formation in LDLr-/- mice. This was associated with reduced infiltration of T cells and macrophages and reduced production of matrix metalloproteinase (MMP)-9. By contrast, the relative smooth muscle cell and collagen content was increased, indicating a more stable plaque phenotype. In addition, we provide evidence for direct inhibition of leukocyte recruitment into aortic root lesions, attenuated leukocyte rolling and arrest in mesenteric vessels, as well as a reduced proinflammatory response following Con A stimulation in vitro. CONCLUSIONS: Interference with chemokine oligomerization and chemokine/heparin interactions is a powerful novel approach that inhibits progression of established atherosclerosis in mice. By inhibiting leukocyte recruitment into plaques, [44AANA47]-RANTES mediates a less inflammatory plaque phenotype and thus reduced systemic inflammatory state.

Keywords
  • Animals
  • Aorta/drug effects/metabolism/pathology
  • Atherosclerosis/metabolism/pathology/prevention & control
  • Chemokine CCL2/metabolism
  • Chemokine CCL5/antagonists & inhibitors
  • Chemokines/pharmacology
  • Collagen/metabolism
  • Disease Models, Animal
  • Disease Progression
  • Heparin/metabolism
  • Leukocytes/drug effects/physiology
  • Male
  • Matrix Metalloproteinase 9/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, CCR2/metabolism
  • Receptors, CCR5/metabolism
  • Receptors, LDL/genetics/metabolism
Citation (ISO format)
BRAUNERSREUTHER, Vincent et al. A novel RANTES antagonist prevents progression of established atherosclerotic lesions in mice. In: Arteriosclerosis, thrombosis, and vascular biology, 2008, vol. 28, n° 6, p. 1090–1096. doi: 10.1161/ATVBAHA.108.165423
Main files (1)
Article (Accepted version)
accessLevelRestricted
Identifiers
ISSN of the journal1079-5642
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