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Selective Tyrosine Kinase Inhibitor for the Platelet-Derived Growth Factor Receptor In Vitro Inhibits Smooth Muscle Cell Proliferation After Reinjury of Arterial Intima In Vivo

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Abstract

Summary. The long-term success of coronary angioplasty is limited by restonosis. This study was undertaken to investigate whether and to what extent the enhanced proliferative response observed in a balloon reinjury model of rat aorta is regulated by the PDGF receptor (PDGF-R). Balloon injury was performed to 14-day-old pre-existing neointimal lesion in rat aorta. PDGF receptor and ligand immunoreactivity were measured at several time points after the first and second injury, and PDGF-R signaling was blocked with a selective inhibitor of PDGF-R tyrosine kinase. In the neointima, after repeated injury, upregulation of PDGF-AA was seen to coincide with a prompt proliferative response of smooth muscle cells (SMC). Administration of the PDGF-R tyrosine kinase inhibitor in vivo, tested and found to inhibit the proliferation of SMC induced by PDGF-AA and PDGF-BB, but not by IGF-1, EGF, or bFGF, resulted in a 60% reduction in the absolute number and percentage of BrdU+ cells after the second balloon injury to pre-existing neointima, but had no significant effect on proliferation after the first injury. Endpoint lesion are was reduced by 50% in the treated group at 14 days after the second injury. The results suggest that systemic administration of a tyrosine kinase inhibitor specific for the PDGF-R can be useful in the prevention of restenosis.

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Authors and Affiliations

  1. Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Marjukka Myllärniemi, Juhana Frösen, Lázaro G. Calderón Ramirez, Karl Lemström & Pekka Häyry;

  2. Novartis Pharmaceuticals Division, Basle, Switzerland

    Elisabeth Buchdunger

Authors
  1. Marjukka Myllärniemi
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  2. Juhana Frösen
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  3. Lázaro G. Calderón Ramirez
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  4. Elisabeth Buchdunger
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  5. Karl Lemström
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  6. Pekka Häyry;
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Myllärniemi, M., Frösen, J., Calderón Ramirez, L.G. et al. Selective Tyrosine Kinase Inhibitor for the Platelet-Derived Growth Factor Receptor In Vitro Inhibits Smooth Muscle Cell Proliferation After Reinjury of Arterial Intima In Vivo. Cardiovasc Drugs Ther 13, 159–168 (1999). https://doi.org/10.1023/A:1007700629728

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