title: Aortic valve calcification is mediated by a differential response of aortic valve interstitial cells to inflammation.
abstract: BACKGROUND
  Although calcific aortic stenosis is common, calcification of the other three heart valves is not. The aortic valve interstitial cell (VIC) has been implicated in the pathogenesis of aortic stenosis. Proinflammatory stimulation of aortic VICs induces an osteogenic and inflammatory phenotypic change. We hypothesized that the VICs of the other heart valves do not undergo these changes. Using isolated human VICs from normal aortic, mitral, pulmonary, and tricuspid valves, our purpose was to compare the osteogenic response to proinflammatory stimulation via toll-like receptor 4 (TLR-4).
  
  
  METHODS
  Aortic, pulmonic, mitral, and tricuspid (n=4 for each valve type) VICs were isolated from hearts valves explanted from patients undergoing cardiac transplantation. Cells were cultured and grown to confluence in passage 2-6 before treatment with Lipopolysaccharide (LPS) (100-200 ng/mL) for 24 or 48 h. Cells were characterized by immunofluorescent staining. TLR-4 expression was analyzed (immunoblotting, flow cytometry). Bone morphogenetic protein 2 and intercellular adhesion molecule 1 production were determined (immunoblotting). Monocyte chemoattractant protein 1 levels were determined by enzyme-linked immunosorbent assay. Statistics were by Mann-Whitney U test.
  
  
  RESULTS
  TLR-4 stimulation induced bone morphogenetic protein 2 production only in aortic VICs (P<0.05). Intra-cellular adhesion molecule 1 production and monocyte chemoattractant protein 1 secretion increased in a similar fashion among TLR-4-stimulated VICs from all four valves.
  
  
  CONCLUSIONS
  Proinflammatory stimulation induces an osteogenic phenotype in aortic VICs but not mitral, pulmonic, or tricuspid VICs. We conclude that this differential osteogenic response of aortic VICs contributes to the pathogenesis of calcific aortic stenosis.
authors.affiliation: The Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine. Electronic address: Neil.Venardos@ucdenver.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Venardos
authors.affiliation: The Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Nadlonek
authors.affiliation: The Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: The Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
authors.affiliation: The Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine.
authors.forename: Thomas Brett
authors.initials: TB
authors.lastname: Reece
authors.affiliation: The Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.affiliation: The Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
mesh_terms: D000328:Adult; D001021:Aortic Valve / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000209:etiology*; D002114:Calcinosis / Q000209:etiology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008875:Middle Aged; D010012:Osteogenesis; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D051197:Toll-Like Receptor 4
keywords: Aortic stenosis; TLR-4; Valve interstitial cell
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