title: Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves.
abstract: OBJECTIVE
  Aortic stenosis (AS) is characterized by extensive remodelling of the valves, including infiltration of inflammatory cells, extracellular matrix degradation, and fibrosis. The molecular mechanisms behind this adverse remodelling have remained obscure. In this article, we study whether cathepsin G, an angiotensin II (Ang II)-forming elastolytic enzyme, contributes to progression of AS.
  
  
  RESULTS
  Stenotic aortic valves (n = 86) and control valves (n = 17) were analysed for cathepsin G, transforming growth factor-beta1 (TGF-beta1), and collagens I and III with RT-PCR and immunohistochemistry. Valvular collagen/elastin ratio was quantified by histochemistry. In stenotic valves, cathepsin G was present in mast cells and showed increased expression (P < 0.001), which correlated positively (P < 0.001) with the expression levels of TGF-beta1 and collagens I and III. TGF-beta1 was also present in mast cell-rich areas and cathepsin G induced losartan-sensitive TGF-beta1 expression in cultured fibroblasts. Collagen/elastin ratio was increased in stenotic valves (P < 0.001) and correlated positively with smoking (P = 0.02). Nicotine in cigarette smoke activated mast cells and induced TGF-beta1 expression in cultured fibroblasts. Fragmented elastin was observed in stenotic valves containing activated cathepsin G-secreting mast cells and in normal valves treated with cathepsin G.
  
  
  CONCLUSIONS
  In stenotic aortic valves, mast cell-derived cathepsin G may cause adverse valve remodelling and AS progression.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Helske
authors.forename: Suvi
authors.initials: S
authors.lastname: Syväranta
authors.forename: Markku
authors.initials: M
authors.lastname: Kupari
authors.forename: Jani
authors.initials: J
authors.lastname: Lappalainen
authors.forename: Mika
authors.initials: M
authors.lastname: Laine
authors.forename: Jyri
authors.initials: J
authors.lastname: Lommi
authors.forename: Heikki
authors.initials: H
authors.lastname: Turto
authors.forename: Mikko
authors.initials: M
authors.lastname: Mäyränpää
authors.forename: Kalervo
authors.initials: K
authors.lastname: Werkkala
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Ken A
authors.initials: KA
authors.lastname: Lindstedt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001024:Aortic Valve Stenosis / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008407:Mast Cells; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012697:Serine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D012906:Smoke; D014026:Nicotiana; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D012906:Smoke; D053773:Transforming Growth Factor beta1; D003094:Collagen; D004549:Elastin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G