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


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.
Braunersreuther
Vincent
V
Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva, Switzerland.
Steffens
Sabine
S
Arnaud
Claire
C
Pelli
Graziano
G
Burger
Fabienne
F
Proudfoot
Amanda
A
Mach
François
F
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors*; D018925:Chemokines / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006493:Heparin / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054390:Receptors, CCR2 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D011973:Receptors, LDL; D006493:Heparin; D003094:Collagen; D020780:Matrix Metalloproteinase 9