title: Adult aortic valve interstitial cells have greater responses to toll-like receptor 4 stimulation.
abstract: BACKGROUND
  Aortic valve interstitial cells (AVICs) have been implicated in the pathogenesis of calcific aortic valve disease. Signal transducer and activator of transcription 3 (Stat3) possesses antiinflammatory effects. Given that calcification occurs in adult valves, we hypothesized that AVICs from adult valves more likely undergo a proosteogenic phenotypic change than those from pediatric valves and that may be related to different Stat3 activation in the response of those two age groups to toll-like receptor 4 (TLR4).
  
  
  METHODS
  AVICs from healthy human aortic valve tissues were treated with TLR4 agonist lipopolysaccharide. Cellular levels of TLR4, intercellular adhesion molecule 1, bone morphogenetic protein 2, and alkaline phosphatase, as well as phosphorylation of p-38 mitogen-activated protein kinase (MAPK), nuclear factor-κβ (NF-κβ), and Stat3, were analyzed.
  
  
  RESULTS
  Toll-like receptor 4 protein levels were comparable between adult and pediatric AVICs. Adult cells produce markedly higher levels of the above markers after TLR4 stimulation, which is negatively associated with phosphorylation of Stat3. Inhibition of Stat3 enhanced p-38 MAPK and NF-κβ phosphorylation and exaggerated the expression of the above markers in pediatric AVICs after TLR4 stimulation.
  
  
  CONCLUSIONS
  Adult AVICs exhibit greater inflammatory and osteogenic responses to TLR4 stimulation. The enhanced responses in adult AVICs are at least partly due to lower levels of Stat3 activation in response to TLR4 stimulation relative to pediatric cells. Stat3 functions as a negative regulator of the TLR4 responses in human AVICs. The results suggest that Stat3 activation (tyrosine phosphorylation) may be protective and that TLR4 inhibition could be targeted pharmacologically to treat calcific aortic valve disease.
authors.affiliation: Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado; Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Deng
authors.affiliation: Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.affiliation: Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: QingChun
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: David
authors.initials: D
authors.lastname: Fullerton
authors.affiliation: Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Max
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado; Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: james.jaggers@childrenscolorado.org.
authors.forename: James
authors.initials: J
authors.lastname: Jaggers
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001021:Aortic Valve / Q000166:cytology*; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000209:etiology; D008875:Middle Aged; D010012:Osteogenesis; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4