A new monocyte chemotactic protein-1/chemokine CC motif ligand-2 competitor limiting neointima formation and myocardial ischemia/reperfusion injury in mice.

摘要

OBJECTIVES: A nonagonist monocyte chemotactic protein-1 (MCP-1/CCL2) mutant (PA508) with increased affinity for glycosaminoglycans and thus competing with CCL2 was evaluated as a candidate for preventing neointima formation or myocardial ischemia/reperfusion injury. BACKGROUND: Myocardial infarction (MI) remains a major cause of death worldwide despite improved interventional and therapeutic options. Therefore, the discovery of drugs that limit restenosis after intervention and post-MI damage remains an important challenge. METHODS: The function of PA508 was assessed in functional assays in vitro and in mouse models of wire-induced neointima formation and experimental MI. RESULTS: PA508 was functionally inactive in CC chemokine receptor 2 (CCR2) binding and calcium influx but inhibited monocyte chemotaxis or transendothelial migration toward CCL2, suggesting that it interferes with CCL2 presentation. In wild-type but not CCR2-deficient mice, PA508 reduced inflammatory leukocyte recruitment without affecting differential leukocyte counts, CCL2 levels, organ function, or morphology, indicating that it specifically attenuates the CCL2-CCR2 axis. Compared with vehicle, daily intraperitoneal injection of PA508 significantly (p < 0.05, n = 5) reduced neointimal plaque area and mononuclear cell infiltration in carotid arteries of hyperlipidemic apolipoprotein E-deficient mice while increasing smooth muscle cell content. In C57Bl/6J mice that underwent myocardial ischemia/reperfusion, treatment with PA508 significantly reduced infarction size, monocyte infiltration, and collagen and myofibroblast content in the infarction area and preserved heart function compared with vehicle (p < 0.05, n = 4 to 8). CONCLUSIONS: Here we demonstrate that administration of a rationally designed CCL2 competitor reduced inflammatory monocyte recruitment, limited neointimal hyperplasia, and attenuated myocardial ischemia/reperfusion injury in mice and could therefore be envisioned as a combined therapeutic approach for restenosis and MI.