title: Prostaglandin I2 induces apoptosis via upregulation of Fas ligand in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.
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 PGI2 at a low concentration. PCR-array analysis revealed that PGI2 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.
authors.affiliation: Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akagi
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Matsubara
authors.forename: Kengo Fukushima
authors.initials: KF
authors.lastname: Kusano
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kataoka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oto
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Miyaji
authors.forename: Aya
authors.initials: A
authors.lastname: Miura
authors.forename: Aiko
authors.initials: A
authors.lastname: Ogawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ueda-Ishibashi
authors.forename: Chikao
authors.initials: C
authors.lastname: Yutani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D011464:Epoprostenol / Q000633:toxicity*; D065627:Familial Primary Pulmonary Hypertension; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D007223:Infant; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D053222:Fas Ligand Protein; D011464:Epoprostenol