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.