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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1090.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

A Novel RANTES Antagonist Prevents Progression of Established Atherosclerotic Lesions in Mice

Vincent Braunersreuther; Sabine Steffens; Claire Arnaud; Graziano Pelli; Fabienne Burger; Amanda Proudfoot; François Mach

From the Division of Cardiology, Department of Medicine (V.B., S.S., C.A., G.P., F.B., F.M.), University Hospital, Foundation for Medical Researches, Geneva, Switzerland; and Geneva Research Centre Merck Serono International S.A., Geneva, Switzerland (A.P.).

Correspondence to François Mach, Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva, Switzerland. E-mail Francois.Mach{at}medecine.unige.ch

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.

Key Words: atherosclerosis • inflammation • leukocytes • chemokines