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 (...

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Published in:	Journal of the American College of Cardiology 2010-11, Vol.56 (22), p.1847-1857
Main Authors:	Liehn, Elisa A., MD, PhD, Piccinini, Anna-Maria, PhD, Koenen, Rory R., PhD, Soehnlein, Oliver, MD, PhD, Adage, Tiziana, PhD, Fatu, Roxana, MD, Curaj, Adelina, BS, Popescu, Alexandra, BS, Zernecke, Alma, MD, Kungl, Andreas J., PhD, Weber, Christian, MD
Format:	Article
Language:	eng
Subjects:	Animals Atherosclerosis Biological and medical sciences Cardiology. Vascular system Cardiovascular Chemokine CCL2 - physiology Chemokines Competition Coronary heart disease Disease Models, Animal Flow cytometry Heart Heart rate inflammation Internal Medicine Ischemia leukocyte Medical sciences Mice Mice, Inbred C57BL myocardial infarction Myocardial Reperfusion Injury - complications Myocarditis. Cardiomyopathies Neointima neointima formation Proteins Studies
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Summary:	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.
ISSN:	0735-1097 1558-3597