Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice.
Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a chemokine pathway in vivo with the CC chemokine antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major chemokines and chemokine receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC chemokine or its receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a chemokine receptor antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease.
Veillard
Niels R
NR
Division Cardiology, Foundation for Medical Research, University Hospital Geneva, Geneva, Switzerland.
Kwak
Brenda
B
Pelli
Graziano
G
Mulhaupt
Flore
F
James
Richard W
RW
Proudfoot
Amanda E I
AE
Mach
François
F
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000633:toxicity; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000502:physiology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011973:Receptors, LDL / Q000172:deficiency; D014657:Vasculitis / Q000473:pathology / Q000517:prevention & control
D001057:Apolipoproteins E; D065100:CCR5 Receptor Antagonists; C515301:Ccr1 protein, mouse; C515335:Ccr2 protein, mouse; D018946:Chemokine CCL5; D018925:Chemokines; D002791:Cholesterol, Dietary; C108335:RANTES, Met-; D012333:RNA, Messenger; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011973:Receptors, LDL