Blockade of CCR3 retains the neutrophils, preserving their survival during healing after myocardial infarction.

BACKGROUND: Chemokines are critical mediators in controlling and monitoring the healing and ventricular remodeling after myocardial infarction (MI). They proved to be valuable targets for therapeutic measures to reduce the scar formation and to preserve heart function in patients suffering MI. In the present study, the role of CCR3 in myocardial ischemia/reperfusion was established. METHODS AND RESULTS: One week after infarct induction in a mouse coronary ligation model, the functional and morphological parameters of the heart were analyzed. Isolated-heart Langendorff perfusion showed no significantly differences in heart function, infarction size and post infarction angiogenesis after CCR3 blockade. Apoptotic, proliferation signals as well as collagen synthesis were not affected in CCR3 antagonist treated mice. Notably, CCR3 inhibition was accompanied by massive neutrophil infiltration, while leaving the presence of other immune cell subsets in heart unaffected. CONCLUSION: Since neutrophils represents one of the most widely explored therapeutic targets in the treatment of cardiac disease, this study may open a new perspective for a better understanding of the physiology and homeostasis of neutrophils and points out new directions for intervention in acute MI.

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

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.