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Title

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

Authors
Proudfoot, Amanda
Published in Arteriosclerosis, Thrombosis, and Vascular Biology. 2008, vol. 28, no. 6, p. 1090-6
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 AnimalsAorta/drug effects/metabolism/pathologyAtherosclerosis/metabolism/pathology/prevention & controlChemokine CCL2/metabolismChemokine CCL5/antagonists & inhibitorsChemokines/pharmacologyCollagen/metabolismDisease Models, AnimalDisease ProgressionHeparin/metabolismLeukocytes/drug effects/physiologyMaleMatrix Metalloproteinase 9/metabolismMiceMice, Inbred C57BLMice, TransgenicReceptors, CCR2/metabolismReceptors, CCR5/metabolismReceptors, LDL/genetics/metabolism
Stable URL http://archive-ouverte.unige.ch/unige:1036
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PMID: 18388327
Structures
Research groups Biologie du myocarde (22)
L'athérosclérose et ses complications cliniques (591)
Le rôle du système endocannabinoïde dans l'athérosclérose (882)
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