Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Int J Cardiol. 2012 Aug 23;159(2):100-6. doi: 10.1016/j.ijcard.2011.02.024. Epub 2011 Mar 4.
Remodeling of the pulmonary artery by an inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) is problematic in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Effective treatment that achieves reverse remodeling is required. The aim of this study was to assess the pro-apoptotic effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PASMCs obtained from patients with IPAH.
PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by (3)H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy.
Treatment with imatinib (0.1 to 10 μg/mL) significantly inhibited PDGF-BB (10 ng/mL)-induced proliferation of PASMCs from IPAH patients. Imatinib (1 μg/mL) did not induce apoptosis in quiescent IPAH-PASMCs, but it had a pro-apoptotic effect on IPAH-PASMCs stimulated with PDGF-BB. Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF-BB stimulation. PDGF-BB induced phosphorylation of Akt at 15 min, and Akt phosphorylation was inhibited by imatinib in IPAH-PASMCs. Akt-I-1/2 (1 μmol/L), an Akt inhibitor, in the presence of PDGF-BB significantly increased apoptotic cells compared with the control condition. Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs.
Imatinib has anti-proliferative and pro-apoptotic effects on IPAH-PASMCs stimulated with PDGF. The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro-apoptotic effect.
肺动脉平滑肌细胞（PASMCs）的不适当增加导致肺动脉重构，这是特发性肺动脉高压（IPAH）治疗中的一个问题。需要有效的逆转重构治疗。本研究旨在评估血小板衍生生长因子（PDGF）受体酪氨酸激酶抑制剂伊马替尼对 IPAH 患者 PASMCs 的促凋亡作用。
从 8 名接受肺移植的 IPAH 患者中获得 PASMCs。通过（3）H-胸腺嘧啶掺入评估细胞增殖。使用 TUNEL 和 caspase-3、7 测定法以及透射电子显微镜检查伊马替尼的促凋亡作用。
伊马替尼（0.1 至 10 μg/mL）治疗显著抑制了 IPAH 患者 PASMCs 对 PDGF-BB（10 ng/mL）诱导的增殖。伊马替尼（1 μg/mL）在静息 IPAH-PASMCs 中不诱导细胞凋亡，但对 PDGF-BB 刺激的 IPAH-PASMCs 具有促凋亡作用。伊马替尼在有无 PDGF-BB 刺激的正常对照 PASMCs 中均不诱导细胞凋亡。PDGF-BB 在 15 分钟诱导 Akt 磷酸化，伊马替尼抑制 IPAH-PASMCs 中的 Akt 磷酸化。在 PDGF-BB 存在下，Akt 抑制剂 Akt-I-1/2（1 μmol/L）与对照条件相比，显著增加了凋亡细胞。因此，Akt-I-1/2 可以模拟伊马替尼对 PASMCs 的作用。
伊马替尼对 PDGF 刺激的 IPAH-PASMCs 具有抗增殖和促凋亡作用。PDGF 诱导的 Akt 磷酸化的抑制作用在促凋亡作用中起重要作用。
