title: Radiation induces osteogenesis in human aortic valve interstitial cells.
abstract: OBJECTIVE
  Irradiation of the chest or chest wall has been shown to cause calcific aortic stenosis. However, the mechanisms are unknown. Aortic valve interstitial cells have been implicated in the pathogenesis of aortic stenosis; they have been shown to change from the phenotype of a myofibroblast to an osteoblastlike cell. We therefore hypothesized that irradiation of human aortic valve interstitial cells induces an osteogenic phenotype. In isolated human aortic valve interstitial cells, our purpose was to determine the effect of irradiation on the production of osteogenic factors: (1) bone morphogenetic protein 2, (2) osteopontin, (3) alkaline phosphatase, and (4) the transcription factor Runx2.
  
  
  METHODS
  Human aortic valve interstitial cells were isolated from normal aortic valves obtained from explanted hearts of patients undergoing cardiac transplantation (n = 4) and were grown in culture. The cells were grown to confluence, irradiated with 10 Gy using a cesium-137 irradiator, and then lysed 24 hours after irradiation. Cell lysates were analyzed via immunoblot and densitometry for bone morphogenetic protein 2, osteopontin, alkaline phosphatase, and Runx2. Statistical analysis was performed using analysis of variance, with P < .05 indicating significance.
  
  
  RESULTS
  Irradiation induced an osteogenic phenotype in human aortic valve interstitial cells. Irradiation induced a 2-fold increase in bone morphogenetic protein 2, a 7-fold increase in osteopontin, a 3-fold increase in alkaline phosphatase, and a 2-fold increase in Runx2.
  
  
  CONCLUSIONS
  Radiation induces an osteogenic phenotype in human aortic valve interstitial cells. The irradiated cells had a significantly increased expression of the osteogenic factors bone morphogenetic protein 2, osteopontin, alkaline phosphatase, and Runx2. These data offer mechanistic insight into the pathogenesis of radiation-induced valvular heart disease.
authors.affiliation: Division of Cardiothoracic Surgery, University of Colorado School of Medicine, Aurora, Colo, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Nadlonek
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Yu
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.forename: T Brett
authors.initials: TB
authors.lastname: Reece
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000378:metabolism; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D001024:Aortic Valve Stenosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010012:Osteogenesis / Q000528:radiation effects*; D053495:Osteopontin / Q000378:metabolism; D010641:Phenotype; D011832:Radiation Injuries / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011878:Radiotherapy / Q000009:adverse effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C525718:BMP2 protein, human; D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; C506895:SPP1 protein, human; D053495:Osteopontin; D000469:Alkaline Phosphatase