Reverse Apolipoprotein A-I Mimetic Peptide R-D4F Inhibits Neointimal Formation following Carotid Artery Ligation in Mice

The ApoA-I mimetic peptide D-4F has demonstrated potent atheroprotective actions in vivo and in vitro. We investigated the effect of R-D4F (ie, the D-4F peptide with reverse order of amino acids) on intimal hyperplasia after vascular injury in a mouse model of carotid artery ligation. Adult male C57BL/6J mice were pretreated intraperitoneally with vehicle, D-4F (1 mg/kg), or R-D4F (1 mg/kg or 5 mg/kg) daily for 3 days; the mice were then subjected to left carotid artery ligation. All treatments were continued for 28 days after surgery. Neither D-4F nor R-D4F treatment affected serum lipid levels. Morphometric analysis showed that the occluded vessels had significant neointimal formation, compared with the uninjured arteries in vehicle-treated mice. Like the D-4F treatment, R-D4F treatment significantly (P < 0.05) inhibited intimal hyperplasia (−42%), local neutrophil and macrophage infiltration, and mRNA expression of the proinflammatory mediator monocyte chemotactic protein 1 (−55%) and vascular cell adhesion protein 1 (−53%), compared with vehicle. Furthermore, the vasoprotective effect of high-dose R-D4F was significantly enhanced, compared with the low dose. In cultured mouse RAW 264.7 macrophages, pretreatment with R-D4F also effectively inhibited lipopolysaccharide-induced leukocyte integrin CD11b expression, a key molecule for leukocyte infiltration. Taken together, these results suggest that R-D4F has significant anti-inflammatory features and facilitates prevention of neointimal formation after vascular injury in mice.