Makiyama Yashiro, Toba Ken, Kato Kiminori, Hirono Satoru, Ozawa Takuya, Saigawa Takashi, Minagawa Shiro, Isoda Manabu, Asami Fuyuki, Ikarashi Noboru, Oda Masato, Moriyama Masato, Higashimura Masutaka, Kitajima Toshiki, Otaki Keita, Aizawa Yoshifusa
Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Tohoku J Exp Med. 2008 Aug;215(4):299-306. doi: 10.1620/tjem.215.299.
Restenosis is a major problem in percutaneous catheter intervention (PCI) for coronary artery stenosis in patients with acute myocardial infarction. Coronary restenosis arises from intimal hyperplasia, i.e., hyperplasia of the vascular smooth muscle cells (SMCs) caused by endothelial cell (EC) damage due to PCI. Drug eluting stent (DES), a novel stent coated with a cell-growth inhibitor, such as rapamycin, has been utilized to block SMC proliferation, but DES also blocks EC repair and thus requires the administration of anti-platelets for a long time to prevent thrombus formation after PCI. Moreover, insufficient prevention of platelet aggregation sometimes induces restenosis after PCI. One of the signal transduction inhibitors, imatinib mesilate, blocks tyrosine kinase activity of platelet-derived growth factor receptor (PDGFR), and therefore it may block the development of neointima through growth inhibition of SMCs without the obstructive effect on EC-repair. We therefore studied the effects of imatinib on neointimal hyperplasia in a balloon injury model of rat carotid arteries. Rats were orally administered with imatinib for 14 days after balloon injury, and sacrificed to analyze the neointimal formation. Intimal hyperplasia was inhibited by imatinib in a dose-dependent manner. Therefore imatinib presumably obstructed the growth of SMCs via interception on growth-signaling of PDGFR. The administration of imatinib after coronary stenting or the use of an imatinib-eluting stent may further reduce the risk of restenosis in patients.
再狭窄是急性心肌梗死患者冠状动脉狭窄经皮导管介入治疗（PCI）中的一个主要问题。冠状动脉再狭窄源于内膜增生，即PCI导致内皮细胞（EC）损伤引起的血管平滑肌细胞（SMC）增生。药物洗脱支架（DES）是一种新型支架，涂有细胞生长抑制剂，如雷帕霉素，已被用于阻止SMC增殖，但DES也会阻碍EC修复，因此需要长时间服用抗血小板药物以防止PCI后血栓形成。此外，血小板聚集预防不足有时会导致PCI后再狭窄。信号转导抑制剂之一甲磺酸伊马替尼可阻断血小板衍生生长因子受体（PDGFR）的酪氨酸激酶活性，因此它可能通过抑制SMC生长来阻断新生内膜的形成，而不会对EC修复产生阻碍作用。因此，我们研究了伊马替尼对大鼠颈动脉球囊损伤模型新生内膜增生的影响。大鼠在球囊损伤后口服伊马替尼14天，然后处死以分析新生内膜形成情况。伊马替尼以剂量依赖性方式抑制内膜增生。因此，伊马替尼可能通过阻断PDGFR的生长信号来阻碍SMC生长。冠状动脉支架置入后给予伊马替尼或使用伊马替尼洗脱支架可能会进一步降低患者再狭窄的风险。
