title: Sunitinib, a small-molecule receptor tyrosine kinase inhibitor, suppresses neointimal hyperplasia in balloon-injured rat carotid artery.
abstract: The migration and proliferation of vascular smooth muscle cells (VSMCs) induced by growth factors play a critical role in in-stent stenosis after percutaneous coronary intervention (PCI). The present study tested the hypothesis that sunitinib malate (sunitinib), a tyrosine kinase inhibitor of multiple receptors for growth factors, can reduce neointimal formation after arterial injury in vivo and sought to reveal the underlying mechanism in vitro. Male Wistar rats with balloon-injured carotid arteries were administered either sunitinib or a vehicle orally for 2 weeks. Sunitinib significantly inhibited neointimal hyperplasia relative to control by reducing active cell proliferation. In cultured human aortic smooth muscle cells (HASMCs), sunitinib significantly inhibited platelet-derived growth factor (PDGF)-induced increases of DNA synthesis, cell proliferation, and migration relative to controls as evaluated by [(3)H] thymidine incorporation, cell number, and the Boyden chamber assay, respectively. Immunoblot analyses showed that sunitinib suppressed phosphorylation of PDGF-BB inducible extracellular signal-regulated kinase and autophosphorylation of PDGF β-receptor, which are the key signaling steps involved in HASMC activation. These results indicate that sunitinib inhibits neointimal formation after arterial injury by suppressing VSMC proliferation and migration presumably through inactivation of PDGF signaling. As such, it may be a potential therapeutic agent, which targets arterial restenosis after PCI.
authors: 1Department of Bioregulation, Nippon Medical School, Kawasaki, Kanagawa, Japan.
authors: So
authors: S
authors: Ishii
authors: Yoshihisa
authors: Y
authors: Okamoto
authors: Harumi
authors: H
authors: Katsumata
authors: Seiko
authors: S
authors: Egawa
authors: Daisuke
authors: D
authors: Yamanaka
authors: Makoto
authors: M
authors: Fukushima
authors: Shiro
authors: S
authors: Minami
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D040262:Receptors, Vascular Endothelial Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D000077210:Sunitinib
keywords: neointima; platelet-derived growth factor; restenosis; sunitinib; vascular smooth muscle cell