Platelet-derived growth factor receptor inhibition reduces allograft arteriosclerosis of heart and aorta in cholesterol-fed rabbits

Sihvola, Roope; Tikkanen, Jussi; Krebs, R.; Aaltola, Eva M.; Buchdunger, Elisabeth; Laitinen, Outi; Koskinen, Petri; Lemström, Karl

doi:10.1097/01.tp.0000045056.82561.0f

Cited by 22 publications

(17 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This prompted us to embark on early studies of an experimental compound, currently known as imatinib mesylate (Glivec), which was developed as a selective inhibitor of the v-Abl, c-Kit and PDGF-R tyrosine kinases. Using this compound at well-tolerated doses (5–50 mg/kg/day) in preclinical models, we demonstrated virtually complete suppression of neointimal hyperplasia triggered by mechanical injury [29], as well as a 50% reduction in TA in cardiac [27, 28] and vascular [28] allografts (relative to cyclosporin A monotherapy). Other recent studies from our laboratory have shown considerable benefit in using this agent in rat models of obliterative bronchiolitis [40] and chronic allograft nephropathy [41].…”

Section: Discussionmentioning

confidence: 99%

Synergistic Suppression of Rat Neointimal Hyperplasia by Rapamycin and Imatinib Mesylate: Implications for the Prevention of Accelerated Arteriosclerosis

et al. 2006

View full text Add to dashboard Cite

Background: Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia. Methods: Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV. Results: Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5–1.5 mg/kg/day) or imatinib (2– 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance. Conclusions: Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic Suppression of Rat Neointimal Hyperplasia by Rapamycin and Imatinib Mesylate: Implications for the Prevention of Accelerated Arteriosclerosis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Several studies have shown that PDGFR inhibitors such as imatinib and AG-1295 are effective in suppressing restenosis and stenosis in experimental animals (Myllarniemi et al, 1999;Fishbein et al, 2000;Sihvola et al, 2003;Levitzki, 2005). Inhibition of PDGFR in VSMCs by imatinib and AG-1295 requires micromolar concentrations (Fishbein et al, 2000;Sanz-Gonzalez et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Besides Bcr-Abl and c-Kit, imatinib also inhibits PDGFR tyrosine kinase Druker et al, 1996). Experiments in animals have shown that imatinib inhibits restenosis after balloon angioplasty and stenosis after allograft (Myllarniemi et al, 1999;Sihvola et al, 2003). Inhibition of PDGFR by imatinib, however, requires micromolar concentrations in cell-based assays Sanz-Gonzalez et al, 2004).…”

mentioning

confidence: 99%

Potent Inhibition of Platelet-Derived Growth Factor-Induced Responses in Vascular Smooth Muscle Cells by BMS-354825 (Dasatinib)

et al. 2006

View full text Add to dashboard Cite

Abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) are key events in the pathogenesis of restenosis that undermine the long-term benefit of widely performed balloon angioplasty and stenting procedures. Platelet-derived growth factor (PDGF) is a potent mitogen and motogen for VSMCs and is known to play a prominent role in the intimal accumulation of smooth muscle cells. In this study, we analyzed the effects of a novel protein tyrosine kinase inhibitor, BMS-354825 (dasatinib), on PDGF-stimulated VSMCs. BMS-354825 is an orally bioavailable dual Src/Bcr-Abl tyrosine kinase inhibitor currently undergoing clinical trials in cancer patients. We found that BMS-354825 inhibited PDGF-stimulated activation of PDGF receptor (PDGFR), STAT3, Akt, and Erk2 in rat A10 VSMCs and in primary cultures of human aortic smooth muscle cells (AoSMCs) at low nanomolar concentrations. The 50% inhibition of the PDGFR␤ tyrosine kinase activity in vitro by BMS-354825 was observed at 4 nM. Direct comparison of BMS-354825 and another PDGFR inhibitor, imatinib (Gleevec, STI571), in VSMCs indicated that BMS-354825 is 67-fold more potent than imatinib in inhibition of PDGFR activation. BMS-354825 also inhibited Src tyrosine kinase in A10 cells. At the cell level, PDGF stimulated migration and proliferation of A10 cells and human AoSMCs, both of which were inhibited by BMS-354825 in a concentration dependent manner in the low nanomolar range. These results suggest that BMS-354825 is a potent inhibitor of PDGF-stimulated VSMC activities and a potential agent for the development of a new therapy for vascular obstructive diseases such as restenosis.

show abstract

“…Despite the universal occurrence of atherosclerosis in the world, the pathogenesis of disease remains incompletely understood. Atherosclerosis can be considered to be a modified form of chronic inflammation induced by lipids (Glass and Witztum, 2001), and many have followed in this path including evidences that numerous cell adhesion molecules and growth factors were determined in the atherosclerotic plaques (Blankenberg et al, 2003;Sihvola et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Time courses of vascular endothelial growth factor and intercellular adhesion molecule-1 expressions in aortas of atherosclerotic rats

et al. 2005

View full text Add to dashboard Cite

Platelet-derived growth factor receptor inhibition reduces allograft arteriosclerosis of heart and aorta in cholesterol-fed rabbits

Abstract: The results of the present study suggest that PDGF-R activation may regulate the development of transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. Thus, PTK inhibitors may provide new strategies for prevention of these fibroproliferative vascular disorders.

Cited by 22 publications

References 17 publications

Synergistic Suppression of Rat Neointimal Hyperplasia by Rapamycin and Imatinib Mesylate: Implications for the Prevention of Accelerated Arteriosclerosis

Synergistic Suppression of Rat Neointimal Hyperplasia by Rapamycin and Imatinib Mesylate: Implications for the Prevention of Accelerated Arteriosclerosis

Potent Inhibition of Platelet-Derived Growth Factor-Induced Responses in Vascular Smooth Muscle Cells by BMS-354825 (Dasatinib)

Time courses of vascular endothelial growth factor and intercellular adhesion molecule-1 expressions in aortas of atherosclerotic rats

Contact Info

Product

Resources

About