title: Cadherin-11 regulates cell-cell tension necessary for calcific nodule formation by valvular myofibroblasts.
abstract: OBJECTIVE
  Dystrophic calcific nodule formation in vitro involves differentiation of aortic valve interstitial cells (AVICs) into a myofibroblast phenotype. Interestingly, inhibition of the kinase MAPK Erk kinase (MEK)1/2 prevents calcific nodule formation despite leading to myofibroblast activation of AVICs, indicating the presence of an additional mechanotransductive component required for calcific nodule morphogenesis. In this study, we assess the role of transforming growth factor β1-induced cadherin-11 expression in calcific nodule formation.
  
  
  RESULTS
  As shown previously, porcine AVICs treated with transforming growth factor β1 before cyclic strain exhibit increased myofibroblast activation and significant calcific nodule formation. In addition to an increase in contractile myofibroblast markers, transforming growth factor β1-treated AVICs exhibit significantly increased expression of cadherin-11. This expression is inhibited by the addition of U0126, a specific MEK1/2 inhibitor. The role of increased cadherin-11 is revealed through a wound assay, which demonstrates increased intercellular tension in transforming growth factor β1-treated AVICs possessing cadherin-11. Furthermore, when small interfering RNA is used to knockdown cadherin-11, calcific nodule formation is abrogated, indicating that robust cell-cell connections are necessary in generating tension for calcific nodule morphogenesis. Finally, we demonstrate enrichment of cadherin-11 in human calcified leaflets.
  
  
  CONCLUSIONS
  These results indicate the necessity of cadherin-11 for dystrophic calcific nodule formation, which proceeds through an Erk1/2-dependent pathway.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, 2213 Garland Ave, 9445 MRB IV, Nashville, TN 37232-0493, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hutcheson
authors.forename: Joseph
authors.initials: J
authors.lastname: Chen
authors.forename: M K
authors.initials: MK
authors.lastname: Sewell-Loftin
authors.forename: Larisa M
authors.initials: LM
authors.lastname: Ryzhova
authors.forename: Charles I
authors.initials: CI
authors.lastname: Fisher
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Su
authors.forename: W David
authors.initials: WD
authors.lastname: Merryman
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006349:Heart Valve Diseases / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009024:Morphogenesis; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D013314:Stress, Mechanical; D013552:Swine; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D053773:Transforming Growth Factor beta1; C086960:osteoblast cadherin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2