Prostaglandin I2 induces apoptosis via upregulation of Fas ligand in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Satoshi Akagi, Kazufumi Nakamura, Hiromi Matsubara, Kengo Fukushima Kusano, Noriyuki Kataoka, Takahiro Oto, Katsumasa Miyaji, Aya Miura, Aiko Ogawa, Masashi Yoshida, Hatsue Ueda-Ishibashi, Chikao Yutani, Hiroshi Ito

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Pulmonary vascular remodeling with idiopathic pulmonary arterial hypertension (IPAH) is associated with impaired apoptosis of pulmonary artery smooth muscle cells (PASMCs). We have reported that high-dose prostaglandin I2 (PGI2) therapy markedly improved hemodynamics in IPAH patients. The therapy is thought to reverse vascular remodeling, though the mechanism is unclear. The aim of this study is to assess proapoptotic effects of PGI2 on PASMCs obtained from IPAH patients. Methods: We investigated proapoptotic effects of PGI2 in PAH-PASMCs by TUNEL assays, caspase-3,-7 assays and transmission electron microscopy. We examined the expression of Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, in PAH-PASMCs. We measured the serum FasL levels in IPAH patients treated with PGI2. Results: TUNEL-positive, caspase-3, 7-active cells and fragmentation of the nucleus were detected in PAH-PASMCs treated with PGI2. The percentage of apoptotic cells induced by PGI2 at a high concentration was higher than that induced by PGI 2 at a low concentration. PCR-array analysis revealed that PGI 2 upregulated the FasL gene in PAH-PASMCs, and we measured the FasL expression by quantitative RT-PCR and Western blotting. PGI2 significantly increased the mRNA level of FasL by 3.98 fold and the protein level of FasL by 1.70 fold. An IP receptor antagonist inhibited the induction of apoptosis, elevation of cyclic AMP and upregulation of FasL by PGI2. Serum FasL level had a significant positive correlation with PGI2 dose in IPAH patients treated with PGI2. Conclusions: PGI2 has proapoptotic effects on PAH-PASMCs via the IP receptor and upregulation of FasL.

Original languageEnglish
Pages (from-to)499-505
Number of pages7
JournalInternational Journal of Cardiology
Volume165
Issue number3
DOIs
Publication statusPublished - Jan 1 2013

Keywords

  • Apoptosis
  • Fas ligand
  • Idiopathic pulmonary arterial hypertension
  • Prostaglandin I
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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