Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo.
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 (35)S-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 approximately 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.
Ballinger
Mandy L
ML
Diabetes & Cell Biology, BakerIDI Heart & Diabetes Institute, Prahran, Australia.
Osman
Narin
N
Hashimura
Kazuhiko
K
de Haan
Judy B
JB
Jandeleit-Dahm
Karin
K
Allen
Terri
T
Tannock
Lisa R
LR
Rutledge
John C
JC
Little
Peter J
PJ
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D001549:Benzamides; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004187:Disaccharides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D050356:Lipid Metabolism / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011509:Proteoglycans / Q000096:biosynthesis*; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism
D001057:Apolipoproteins E; D001549:Benzamides; D004041:Dietary Fats; D004187:Disaccharides; D006025:Glycosaminoglycans; D008077:Lipoproteins, LDL; D010879:Piperazines; D011509:Proteoglycans; D011743:Pyrimidines; D013455:Sulfur; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor