title: Trichostatin A, an HDAC class I/II inhibitor, promotes Pi-induced vascular calcification via up-regulation of the expression of alkaline phosphatase.
abstract: OBJECTIVE
  Vascular calcification, a major complication of chronic kidney disease (CKD), refers to the mineralization of vascular smooth muscle cells (VSMCs), resulting from a phenotypic change towards osteoblast-like cells. Histone deacetylase inhibitors (HDIs), potential therapeutic agents for CKD, are known to promote the differentiation and mineralization of osteoblasts. In this study, we aimed to determine the effects of an HDI on the phenotypic change of VSMCs and the development of vascular calcification.
  
  
  METHODS
  The effect of trichostatin A (TSA), an HDI, on human aortic smooth muscle cells (HASMCs) was determined. The mineralization of HASMCs was induced by inorganic phosphorus (Pi), and was confirmed by quantitation of Ca levels and by von Kossa staining. Furthermore, we examined the effect of alkaline phosphatase (ALP) suppression using siRNA on Pi-induced vascular calcification in the presence or absence of TSA.
  
  
  RESULTS
  TSA increased the expression and activity of ALP in HASMCs at a concentration which showed an inhibitory effect of histone deacetylase (HDAC) activity but not on cell viability. Moreover, TSA promoted the Pi-induced mineralization of HASMCs. In addition, both phosphonoformic acid (PFA), which is a sodium-dependent phosphate transporter inhibitor, and suppression of ALP expression by siRNA markedly inhibited the TSA-promoted mineralization of HASMCs.
  
  
  CONCLUSIONS
  These data show that inhibition of HDAC activity promotes Pi-induced vascular calcification via the up-regulation of ALP expression. Taken together, HDIs may increase the risk of vascular calcification in CKD patients.
authors.affiliation: Department of Clinical Chemistry, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Azechi
authors.forename: Dan
authors.initials: D
authors.lastname: Kanehira
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Ryo
authors.initials: R
authors.lastname: Sudo
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishimura
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wachi
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002114:Calcinosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010710:Phosphates / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010710:Phosphates; D034741:RNA, Small Interfering; C012589:trichostatin A; D000469:Alkaline Phosphatase