Radiation induces osteogenesis in human aortic valve interstitial cells

J Thorac Cardiovasc Surg. 2012 Dec;144(6):1466-70. doi: 10.1016/j.jtcvs.2012.08.041. Epub 2012 Sep 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alkaline Phosphatase / metabolism
  • Aortic Valve / metabolism
  • Aortic Valve / pathology
  • Aortic Valve / radiation effects*
  • Aortic Valve Stenosis / etiology*
  • Aortic Valve Stenosis / metabolism
  • Aortic Valve Stenosis / pathology
  • Biomarkers / metabolism
  • Bone Morphogenetic Protein 2 / metabolism
  • Cells, Cultured
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Humans
  • Male
  • Middle Aged
  • Osteogenesis / radiation effects*
  • Osteopontin / metabolism
  • Phenotype
  • Radiation Injuries / etiology*
  • Radiation Injuries / metabolism
  • Radiation Injuries / pathology
  • Radiotherapy / adverse effects
  • Time Factors
  • Up-Regulation

Substances

  • BMP2 protein, human
  • Biomarkers
  • Bone Morphogenetic Protein 2
  • Core Binding Factor Alpha 1 Subunit
  • RUNX2 protein, human
  • SPP1 protein, human
  • Osteopontin
  • Alkaline Phosphatase