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 [(44)AANA(47)]-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 [(44)AANA(47)]-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, [(44)AANA(47)]-RANTES mediates a less inflammatory plaque phenotype and thus reduced systemic inflammatory state.