Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 99, Issue 6, Pages 1553-1563Publisher
WILEY-LISS
DOI: 10.1002/jcb.20993
Keywords
venous smooth muscle cell; vascular graft; platelet-derived growth factor; Akt; receptor tyrosine kinase inhibitor
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Funding
- NHLBI NIH HHS [R01 HL 67646, R01 HL067646] Funding Source: Medline
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Platelet-derived growth factor (PDGF) has been implicated in smooth muscle cell (SMC) proliferation, a key event in the development of myointimal hyperplasia in vascular grafts. Recent evidence suggests that the PDGF receptor (PDGFR)tyrosine kinase inhibitor, imatinib, can prevent arterial proliferative diseases. Because hyperplasia is far more common at the venous anastomosis than the arterial anastomosis in vascular grafts, we investigated whether imatinib also inhibited venous SMC (VSMC) proliferation, and examined possible differences in its mechanism of action between VSMC and arterial SMC (ASMC). Human ASMC and VSMC were stimulated with PDGF-AB, in the presence or absence of imatinib (0.1-10 mu M). Proliferation was assayed using the 5-bromo-2-deoxyuridine (BrdU) incorporation assay, while PDGFR, Akt and ERK1/2-mitogen activated protein kinase (MAPK) signaling pathways were investigated by immunoblotting. The proliferative response to PDGF at 50 and 100 ng/ml was 32 and 43% greater, respectively, in VSMC than in ASMC. Similarly, PDGF-stimulated proliferation was more sensitive to inhibition by imatinib in VSMC than ASMC (IC50 = 0.05 mu M vs. 0.4 mu M; P < 0.01). Imatinib also more effectively inhibited PDGF-induced phosphorylation of PDGFR beta and Akt in VSMC, compared to ASMC. These data highlight inherent pharmacodynamic differences between VSMC and ASMC in receptor and cell signaling functions and suggest that imatinib therapy may be useful for the prevention of venous stenosis in vascular grafts. J. Cell. Biochem. 99: 1553-1563, 2006. (c) 2006 Wiley-Liss, Inc.
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