Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo

Mandy L. Ballinger, Narin Osman, Kazuhiko Hashimura, Judy B de Haan, Karin Jandeleit-Dahm, Terri Allen, Lisa R. Tannock, John C Rutledge, Peter J. Little

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

The 'response to retention' hypothesis of atherogenesis proposes that proteoglycans bind and retain low-density lipoproteins (LDL) in the vessel wall. Platelet-derived growth factor (PDGF) is strongly implicated in atherosclerosis and stimulates proteoglycan synthesis. Here we investigated the action of the PDGF receptor inhibitor imatinib on PDGF-mediated proteoglycan biosynthesis in vitro, lipid deposition in the aortic wall in vivo and the carotid artery ex vivo. In human vSMCs, imatinib inhibited PDGF mediated 35S-SO 4 incorporation into proteoglycans by 31% (P < 0.01) and inhibited PDGF-mediated size increases in both chemically cleaved and xyloside associated glycosaminoglycan (GAG) chains by 19%, P < 0.05 and 27%, P < 0.05, respectively. Imatinib decreased PDGF stimulation of the 6:4 position sulphation ratio of disaccharides. The half maximal saturation value for LDL binding for proteoglycans from PDGF stimulated cells in the presence of imatinib was approximately 2.5-fold higher than for PDGF treatment alone. In high fat fed ApoE -/- mice, imatinib reduced total lipid staining area by ∼31% (P < 0.05). Carotid artery lipid accumulation in imatinib treated mice was also reduced. Furthermore, we demonstrate that imatinib inhibits phosphorylation of tyrosine 857, the autophosphorylation site of the PDGF receptor, in vSMCs. Thus imatinib inhibits GAG synthesis on vascular proteoglycans and reduces LDL binding in vitro and in vivo and this effect is mediated via the PDGF receptor. These findings validate a novel mechanism to prevent cardiac disease.

Original languageEnglish (US)
Pages (from-to)1408-1418
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume14
Issue number6 B
DOIs
StatePublished - Jun 2010

Keywords

  • Atherosclerosis
  • Glycosaminoglycans
  • Protein tyrosine kinase
  • Proteoglycans
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

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