© 2000 American Heart Association, Inc.
Vascular Biology |
Local Delivery of Platelet-Derived Growth Factor Receptor–Specific Tyrphostin Inhibits Neointimal Formation in Rats
From the Department of Pharmaceutics (I.F., L.R., M.C., G.G.), School of Pharmacy, Faculty of Medicine, the Department of Biological Chemistry (A.L., A.G.), Institute of Life Sciences, and the Department of Anatomy and Cell Biology (S.D.G.), The Hebrew University of Jerusalem, Jerusalem, Israel; the Department of Internal Medicine II (Cardiology) (J.W., R.H., U.M.), Ulm University Medical Center, Ulm, Germany; and the Department of Cardiology (S.B.), Bikur Cholim Hospital, Jerusalem, Israel.
Correspondence to Dr Gershon Golomb, Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E-mail golomb{at}cc.huji.ac.il
Abstract—Signal transduction through the platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) system is involved in the process of postangioplasty restenosis. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases. We assessed the antiproliferative effects of PDGFRß-specific tyrphostin AG-1295 in vitro and in vivo. AG-1295 significantly inhibited rat smooth muscle cell growth stimulated by PDGF-BB or FCS. This antiproliferative effect was paralleled by reversible reduction of the total phosphotyrosine level and the degree of PDGFRß phosphorylation by the drug in vitro. Local sustained delivery of the drug from perivascularly implanted polymeric matrices resulted in focal AG-1295 levels of 711 and 29.1 ng/mg of dry arterial tissue 1 and 14 days after implantation in rats. AG-1295 delivered from polymeric matrices resulted in a 35% reduction of neointimal formation on day 14 after balloon injury in the rat carotid model. Tyrosine phosphorylation of certain transduction proteins in arterial tissue extracts was significantly upregulated by balloon injury on day 3 but was essentially returned to or below basal levels 14 days after injury. Tyrphostin treatment decreased tyrosine phosphorylation at both time points below the basal levels. Moreover, the enhancement of PDGFRß expression 3 and 14 days after arterial injury was strongly inhibited by AG-1295 treatment. It can be concluded that AG-1295 reduces neointimal formation by inhibiting PDGFß-triggered tyrosine phosphorylation.
Key Words: restenosis • protein tyrosine kinase • controlled release • platelet-derived growth factor • tyrphostins
This article has been cited by other articles:
 |
|
 |
|
  J. Sparwel, M. Vantler, E. Caglayan, K. Kappert, J. W.U. Fries, H. Dietrich, M. Bohm, E. Erdmann, and S. Rosenkranz Differential effects of red and white wines on inhibition of the platelet-derived growth factor receptor: impact of the mash fermentation Cardiovasc Res, March 1, 2009; 81(4): 758 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zhuang, Q. Pu, B. Ceacareanu, Y. Chang, M. Dixit, and A. Hassid Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H163 - H173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Chen, F. Y. Lee, K. N. Bhalla, and J. Wu Potent Inhibition of Platelet-Derived Growth Factor-Induced Responses in Vascular Smooth Muscle Cells by BMS-354825 (Dasatinib) Mol. Pharmacol., May 1, 2006; 69(5): 1527 - 1533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kappert, E. Caglayan, M. Huntgeburth, A. T. Baumer, J. Sparwel, M. Uebel, and S. Rosenkranz 17{beta}-Estradiol attenuates PDGF signaling in vascular smooth muscle cells at the postreceptor level Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H538 - H546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Reinhardt, T. Mertens, U. Mayr-Beyrle, H. Frank, A. Luske, K. Schierling, and J. Waltenberger HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF {beta}-receptor Cardiovasc Res, July 1, 2005; 67(1): 151 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Levitzki PDGF receptor kinase inhibitors for the treatment of restenosis Cardiovasc Res, February 15, 2005; 65(3): 581 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Banai, S.D. Gertz, L. Gavish, M. Chorny, L. S. Perez, G. Lazarovichi, M. Ianculuvich, M. Hoffmann, M. Orlowski, G. Golomb, et al. Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries Cardiovasc Res, October 1, 2004; 64(1): 165 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Kopp, T. Holzenbein, S. Steiner, R. Marculescu, H. Bergmeister, D. Seidinger, I. Mosberger, C. Kaun, M. Cejna, R. Horvat, et al. Inhibition of restenosis by tissue factor pathway inhibitor: in vivo and in vitro evidence for suppressed monocyte chemoattraction and reduced gelatinolytic activity Blood, March 1, 2004; 103(5): 1653 - 1661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. D. Danenberg, I. Fishbein, J. Gao, J. Monkkonen, R. Reich, I. Gati, E. Moerman, and G. Golomb Macrophage Depletion by Clodronate-Containing Liposomes Reduces Neointimal Formation After Balloon Injury in Rats and Rabbits Circulation, July 30, 2002; 106(5): 599 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fishbein, M. Chorny, S. Banai, A. Levitzki, H. D. Danenberg, J. Gao, X. Chen, E. Moerman, I. Gati, V. Goldwasser, et al. Formulation and Delivery Mode Affect Disposition and Activity of Tyrphostin-Loaded Nanoparticles in the Rat Carotid Model Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1434 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Leppanen, N. Janjic, M.-A. Carlsson, K. Pietras, M. Levin, C. Vargeese, L. S. Green, D. Bergqvist, A. Ostman, and C.-H. Heldin Intimal Hyperplasia Recurs After Removal of PDGF-AB and -BB Inhibition in the Rat Carotid Artery Injury Model Arterioscler Thromb Vasc Biol, November 1, 2000; 20 (11): e89 - e95. [Abstract] [Full Text] [PDF]
|
|