title: A new monocyte chemotactic protein-1/chemokine CC motif ligand-2 competitor limiting neointima formation and myocardial ischemia/reperfusion injury in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Piccinini
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.forename: Tiziana
authors.initials: T
authors.lastname: Adage
authors.forename: Roxana
authors.initials: R
authors.lastname: Fatu
authors.forename: Adelina
authors.initials: A
authors.lastname: Curaj
authors.forename: Alexandra
authors.initials: A
authors.lastname: Popescu
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kungl
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D058426:Neointima
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2