Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Kazufumi Nakamura, Satoshi Akagi, Aiko Ogawa, Kengo F. Kusano, Hiromi Matsubara, Daiji Miura, Soichiro Fuke, Nobuhiro Nishii, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Aya Miura, Chikao Yutani, Tohru Ohe, Hiroshi Itoh

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Abstract

Background: 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. Methods: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by 3H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)100-106
Number of pages7
JournalInternational Journal of Cardiology
Volume159
Issue number2
DOIs
Publication statusPublished - Aug 23 2012

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Platelet-Derived Growth Factor
Pulmonary Artery
Smooth Muscle Myocytes
Phosphorylation
Imatinib Mesylate
Familial Primary Pulmonary Hypertension
Apoptosis
Caspase 7
Lung Transplantation
In Situ Nick-End Labeling
Transmission Electron Microscopy
Caspase 3
Thymidine
Therapeutics
Cell Proliferation
platelet-derived growth factor BB

Keywords

  • Apoptosis
  • Hypertension
  • Pulmonary
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. / Nakamura, Kazufumi; Akagi, Satoshi; Ogawa, Aiko; Kusano, Kengo F.; Matsubara, Hiromi; Miura, Daiji; Fuke, Soichiro; Nishii, Nobuhiro; Nagase, Satoshi; Kohno, Kunihisa; Morita, Hiroshi; Oto, Takahiro; Yamanaka, Ryutaro; Otsuka, Fumio; Miura, Aya; Yutani, Chikao; Ohe, Tohru; Itoh, Hiroshi.

In: International Journal of Cardiology, Vol. 159, No. 2, 23.08.2012, p. 100-106.

Research output: Contribution to journalArticle

Nakamura, Kazufumi ; Akagi, Satoshi ; Ogawa, Aiko ; Kusano, Kengo F. ; Matsubara, Hiromi ; Miura, Daiji ; Fuke, Soichiro ; Nishii, Nobuhiro ; Nagase, Satoshi ; Kohno, Kunihisa ; Morita, Hiroshi ; Oto, Takahiro ; Yamanaka, Ryutaro ; Otsuka, Fumio ; Miura, Aya ; Yutani, Chikao ; Ohe, Tohru ; Itoh, Hiroshi. / Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. In: International Journal of Cardiology. 2012 ; Vol. 159, No. 2. pp. 100-106.
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abstract = "Background: 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. Methods: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by 3H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. Results: 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. Conclusion: 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.",
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AU - Nakamura, Kazufumi

AU - Akagi, Satoshi

AU - Ogawa, Aiko

AU - Kusano, Kengo F.

AU - Matsubara, Hiromi

AU - Miura, Daiji

AU - Fuke, Soichiro

AU - Nishii, Nobuhiro

AU - Nagase, Satoshi

AU - Kohno, Kunihisa

AU - Morita, Hiroshi

AU - Oto, Takahiro

AU - Yamanaka, Ryutaro

AU - Otsuka, Fumio

AU - Miura, Aya

AU - Yutani, Chikao

AU - Ohe, Tohru

AU - Itoh, Hiroshi

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N2 - Background: 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. Methods: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by 3H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. Results: 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. Conclusion: 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.

AB - Background: 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. Methods: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by 3H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. Results: 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. Conclusion: 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.

KW - Apoptosis

KW - Hypertension

KW - Pulmonary

KW - Remodeling

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