title: Metallothionein-dependent up-regulation of TGF-β2 participates in the remodelling of the myxomatous mitral valve.
abstract: OBJECTIVE
  Although an excessive extracellular matrix remodelling has been well described in myxomatous mitral valve (MMV), the underlying pathogenic mechanisms remain largely unknown. Our goal was to identify dysregulated genes in human MMV and then to evaluate their functional role in the progression of the disease.
  
  
  RESULTS
  Dysregulated genes were investigated by transcriptomic, immunohistochemistry, and western blot analyses of the P2 segment collected from human idiopathic MMV during valvuloplasty (n = 23) and from healthy control valves (n = 17). The most striking results showed a decreased expression of two families of genes: the metallothioneins-1 and -2 (MT1/2) and members of the ADAMTS. The mechanistic consequences of the reduced level of MT1/2 were evaluated by silencing their expression in normal valvular interstitial cells (VICs) cultures. The knock-down of MT1/2 resulted in the up-regulation of transforming growth factor-beta 2 (TGF-β2). Most importantly, TGF-β2 was also found significantly increased in MMV tissues. The activation of VICs in vitro by TGF-β2 induced a down-regulation of ADAMTS-1 and an accumulation of versican as observed in human MMV.
  
  
  CONCLUSIONS
  Our studies demonstrate for the first time that MMV are characterized by reduced levels of MT1/2 accompanied by an up-regulation of TGF-β2. In turn, increased TGF-β2 signalling induces down-regulation of aggrecanases and up-regulation of versican, two co-operating processes that potentially participate in the development of the pathology.
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, Tour de Pathologie, B23/3, B-4000 Sart-Tilman, Belgium. ahulin@ulg.ac.be
authors.forename: Alexia
authors.initials: A
authors.lastname: Hulin
authors.forename: Christophe F
authors.initials: CF
authors.lastname: Deroanne
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lambert
authors.forename: Bruno
authors.initials: B
authors.lastname: Dumont
authors.forename: Vincent
authors.initials: V
authors.lastname: Castronovo
authors.forename: Jean-Olivier
authors.initials: JO
authors.lastname: Defraigne
authors.forename: Betty V
authors.initials: BV
authors.lastname: Nusgens
authors.forename: Marc A
authors.initials: MA
authors.lastname: Radermecker
authors.forename: Alain C
authors.initials: AC
authors.lastname: Colige
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071097:ADAMTS1 Protein; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D008875:Middle Aged; D008943:Mitral Valve / Q000378:metabolism*; D008944:Mitral Valve Insufficiency / Q000378:metabolism* / Q000503:physiopathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*; D053675:Versicans / Q000378:metabolism
chemical_list: C541541:MT1E protein, human; C499629:MT1G protein, human; C491053:MT2A protein, human; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; C508322:VCAN protein, human; C407523:metallothionein isoform 1; D053675:Versicans; D008668:Metallothionein; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human