A New Monocyte Chemotactic Protein-1/Chemokine CC Motif Ligand-2 Competitor Limiting Neointima Formation and Myocardial Ischemia/Reperfusion Injury in Mice

Elisa A. Liehn, Anna-Maria Piccinini, Rory R. Koenen, Oliver Soehnlein, Tiziana Adage, Roxana Fatu, Adelina Curaj, Alexandra Popescu, Alma Zernecke, Andreas J. Kungl, Christian Weber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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 hyper-lipidemic apolipoprotein E-deficient mice while increasing smooth muscle cell content. In C57BI/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. (J Am Coll Cardiol 2010;56:1847-57)
Original languageEnglish
Pages (from-to)1847-1857
JournalJournal of the American College of Cardiology
Volume56
Issue number22
DOIs
Publication statusPublished - 23 Nov 2010

Keywords

  • chemokines
  • inflammation
  • leukocyte
  • myocardial infarction
  • neointima formation

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