Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo
Open Access
- 1 June 2010
- journal article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 14 (6b), 1408-1418
- https://doi.org/10.1111/j.1582-4934.2009.00902.x
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-SO4 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.Keywords
This publication has 46 references indexed in Scilit:
- Site-Specific Antiatherogenic Effect of the Antioxidant Ebselen in the Diabetic Apolipoprotein E–Deficient MouseArteriosclerosis, Thrombosis, and Vascular Biology, 2009
- Imatinib Mesylate Reduces Endoplasmic Reticulum Stress and Induces Remission of Diabetes in db/db MiceDiabetes, 2009
- Potential of Small Molecule Protein Tyrosine Kinase Inhibitors as Immunomodulators and Inhibitors of the Development of DiabetesThe Scientific World Journal, 2009
- Biosynthesis of Natural and Hyperelongated Chondroitin Sulfate Glycosaminoglycans: New Insights into an Elusive ProcessThe Open Biochemistry Journal, 2008
- Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinibBlood, 2005
- Varied low density lipoprotein binding property of proteoglycans synthesized by vascular smooth muscle cells cultured on extracellular matrixAtherosclerosis, 2005
- LRP and PDGF Signaling: A Pathway to AtherosclerosisTrends in Cardiovascular Medicine, 2004
- Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine KinaseScience, 2000
- The pathogenesis of atherosclerosis: a perspective for the 1990sNature, 1993
- Production of Platelet-Derived Growth Factor–like Mitogen by Smooth-Muscle Cells from Human AtheromaThe New England Journal of Medicine, 1988