title: Aortic valvular interstitial cells apoptosis and calcification are mediated by TNF-related apoptosis-inducing ligand.
abstract: OBJECTIVE
  Calcific aortic valvular disease (CAVD) is an actively regulated process characterized by the activation of specific osteogenic signaling pathways and apoptosis. We evaluated the involvement in CAVD of the TNF-related apoptosis-inducing ligand (TRAIL), an apoptotic molecule which induces apoptosis by interacting with the death receptor (DR)-4 and DR5, and whose activity is modulated by the decoy receptor (DcR)-1 and DcR2.
  
  
  METHODS
  Sections of calcific and normal aortic valves, obtained at surgery time, were subjected to immunohistochemistry and confocal microscopy for TRAIL immunostaining. Valvular interstitial cells (VICs) isolated from calcific (C-VICs) and normal (N-VICs) aortic valves were investigated for the gene and protein expression of TRAIL receptors. Cell viability was assayed by MTT. Von Kossa staining was performed to verify C-VIC ability to produce mineralized nodules. TRAIL serum levels were detected by ELISA.
  
  
  RESULTS
  Higher levels of TRAIL were detected in calcific aortic valves and in sera from the same patients respect to controls. C-VICs express significantly higher mRNA and protein levels of DR4, DR5, DcR1, DcR2 and Runx2 compared to N-VICs. C-VICs and N-VICs, cultured in osteogenic medium, express significantly higher mRNA levels of DR4, Runx2 and Osteocalcin compared to baseline. C-VICs and N-VICs were sensitive to TRAIL-apoptotic effect at baseline and after osteogenic differentiation, as demonstrated by MTT assay and caspase-3 activation. TRAIL enhanced mineralized matrix nodule synthesis by C-VICs cultured in osteogenic medium.
  
  
  CONCLUSIONS
  TRAIL is characteristically present within calcific aortic valves, and mediates the calcification of aortic valve interstitial cells in culture through mechanism involving apoptosis.
authors.affiliation: Department of Emergencies and Organ Transplantation (DETO), Division of Cardiac Surgery, University "Aldo Moro" of Bari, Italy; Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University "Aldo Moro" of Bari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Galeone
authors.forename: Giacomina
authors.initials: G
authors.lastname: Brunetti
authors.forename: Angela
authors.initials: A
authors.lastname: Oranger
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Adriana
authors.initials: A
authors.lastname: Di Benedetto
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mori
authors.forename: Silvia
authors.initials: S
authors.lastname: Colucci
authors.forename: Alberta
authors.initials: A
authors.lastname: Zallone
authors.forename: Domenico
authors.initials: D
authors.lastname: Paparella
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000166:cytology* / Q000502:physiology*; D001024:Aortic Valve Stenosis / Q000473:pathology*; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D061205:Vascular Calcification / Q000473:pathology*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: Aortic calcification; Apoptosis; TRAIL