Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Tetsuya Ikeda, Kazufumi Nakamura, Satoshi Akagi, Kengo Fukushima Kusano, Hiromi Matsubara, Hideki Fujio, Aiko Ogawa, Aya Miura, Daiji Miura, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Hiroshi Date, Tohru Ohe, Hiroshi Itoh

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet-derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3-hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by H-thymidine incorporation. Simvastatin (0.1 μmol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 μmol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 μmol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects on inappropriate PDGF signaling in PASMCs from patients with IPAH.

Original languageEnglish
Pages (from-to)39-48
Number of pages10
JournalJournal of Cardiovascular Pharmacology
Volume55
Issue number1
DOIs
Publication statusPublished - Jan 2010

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Simvastatin
Platelet-Derived Growth Factor
Pulmonary Artery
Smooth Muscle Myocytes
Familial Primary Pulmonary Hypertension
Lung Transplantation
Arterioles
Coenzyme A
Thymidine
Fluorescent Antibody Technique
Actins
Cell Cycle
Oxidoreductases
Cytoplasm
Western Blotting
Cell Proliferation
Staining and Labeling
Lung
Membranes

Keywords

  • PDGF
  • Pulmonary hypertension
  • Smooth muscle cells
  • Statin

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. / Ikeda, Tetsuya; Nakamura, Kazufumi; Akagi, Satoshi; Kusano, Kengo Fukushima; Matsubara, Hiromi; Fujio, Hideki; Ogawa, Aiko; Miura, Aya; Miura, Daiji; Oto, Takahiro; Yamanaka, Ryutaro; Otsuka, Fumio; Date, Hiroshi; Ohe, Tohru; Itoh, Hiroshi.

In: Journal of Cardiovascular Pharmacology, Vol. 55, No. 1, 01.2010, p. 39-48.

Research output: Contribution to journalArticle

Ikeda, Tetsuya ; Nakamura, Kazufumi ; Akagi, Satoshi ; Kusano, Kengo Fukushima ; Matsubara, Hiromi ; Fujio, Hideki ; Ogawa, Aiko ; Miura, Aya ; Miura, Daiji ; Oto, Takahiro ; Yamanaka, Ryutaro ; Otsuka, Fumio ; Date, Hiroshi ; Ohe, Tohru ; Itoh, Hiroshi. / Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. In: Journal of Cardiovascular Pharmacology. 2010 ; Vol. 55, No. 1. pp. 39-48.
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