title: Phosphatidylinositol 3-kinase/Akt pathway regulates inflammatory mediators-induced calcification of human vascular smooth muscle cells.
abstract: BACKGROUND
  Vascular calcification is a clinically significant component of atherosclerosis and may be promoted by inflammatory stimuli. Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is involved in the regulation of cell metabolism, survival, migration, and inflammatory responses in various cell types.
  
  
  METHODS
  In this study, we investigated the roles of PI3K/Akt signaling pathway in human vascular smooth muscle cell (HVSMC) calcification induced by the inflammatory mediators (IM) including interferon-gamma, tumor necrosis factor-alpha, oncostatin M, and 1alpha,25-dihydroxyvitamin D3.
  
  
  RESULTS
  Pharmacological inhibition of PI3K with wortmannin dose-dependently increased IM-induced HVSMC calcification. IM-induced expression of alkaline phosphatase (ALP) in HVSMC was also augmented by wortmannin, while wortmannin did not induce apoptosis of HVSMCs in the presence or absence of IM. Moreover, wortmannin inhibited Akt activation in HVSMC by shortterm exposure to IM. Overexpression of wild-type or dominant-negative forms of Akt significantly attenuated or enhanced IM-induced ALP expression in HVSMC, respectively. Furthermore, suppression of Akt with siRNA significantly intensified IM-induced ALP expression in HVSMC.
  
  
  CONCLUSIONS
  These data suggest that PI3K/Akt pathway may play an inhibitory role in IM-induced HVSMC calcification through regulating ALP expression.
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. m1152952@med.osaka-cu.ac.jp
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okazaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shioi
authors.forename: Kaname
authors.initials: K
authors.lastname: Hirowatari
authors.forename: Hidenori
authors.initials: H
authors.lastname: Koyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Ishimura
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nishizawa
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D002114:Calcinosis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D002117:Calcitriol / Q000009:adverse effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018836:Inflammation Mediators / Q000009:adverse effects*; D007371:Interferon-gamma / Q000009:adverse effects; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000503:physiopathology*; D053683:Oncostatin M / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects; D000077191:Wortmannin
chemical_list: D000469:Alkaline Phosphatase; D000730:Androstadienes; D002117:Calcitriol; D018836:Inflammation Mediators; D007371:Interferon-gamma; D053683:Oncostatin M; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin