Selective tyrosine kinase inhibitor for the platelet-derived growth factor receptor in vitro inhibits smooth muscle cell proliferation after reinjury of arterial intima in vivo.
The long-term success of coronary angioplasty is limited by restonosis. This study was undertaken to investigate whether and to what extent the enhanced proliferative response observed in a balloon reinjury model of rat aorta is regulated by the PDGF receptor (PDGF-R). Balloon injury was performed to 14-day-old pre-existing neointimal lesion in rat aorta. PDGF receptor and ligand immunoreactivity were measured at several time points after the first and second injury, and PDGF-R signaling was blocked with a selective inhibitor of PDGF-R tyrosine kinase. In the neointima, after repeated injury, upregulation of PDGF-AA was seen to coincide with a prompt proliferative response of smooth muscle cells (SMC). Administration of the PDGF-R tyrosine kinase inhibitor in vivo, tested and found to inhibit the proliferation of SMC induced by PDGF-AA and PDGF-BB, but not by IGF-1, EGF, or bFGF, resulted in a 60% reduction in the absolute number and percentage of BrdU + cells after the second balloon injury to pre-existing neointima, but had no significant effect on proliferation after the first injury. Endpoint lesion area was reduced by 50% in the treated group at 14 days after the second injury. The results suggest that systemic administration of a tyrosine kinase inhibitor specific for the PDGF-R can be useful in the prevention of restenosis.
Myllärniemi
M
M
Transplantation Laboratory, University of Helsinki, Finland. Marjukka.Myllarniemi@Helsinki.Fi
Frösen
J
J
Calderón Ramirez
L G
LG
Buchdunger
E
E
Lemström
K
K
Häyry
P
P
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D000068877:Imatinib Mesylate; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000293:injuries; D010879:Piperazines / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects*; D019233:Retreatment; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor