Increased expression of elastolytic cathepsins S, K, and V and their inhibitor cystatin C in stenotic aortic valves.
OBJECTIVE
To investigate the possible role of elastolytic cathepsins S, K, and V and their endogenous inhibitor cystatin C in adverse extracellular matrix remodeling of stenotic aortic valves.


RESULTS
Stenotic aortic valves were collected at valve replacement surgery and control valves at cardiac transplantations. The expression of cathepsins S, K, and V and cystatin C was studied by conventional and real-time polymerase chain reaction and by immunohistochemistry. Total cathepsin activity in the aortic valves was quantified by a fluorometric microassay. When compared with control valves, stenotic valves showed increased mRNA expression of cathepsins S, K, and V (P<0.05 for each) and a higher total cathepsin activity (P<0.001). In stenotic valves, cystatin C mRNA was increased (P<0.05), and cystatin C protein was found particularly in areas with infiltrates of inflammatory cells. Both cathepsin S and cystatin C were present in bony areas of the valves, whereas cathepsin V localized to endothelial cells in areas rich of neovascularization. Incubation of thin sections of aortic valves with cathepsins S, K, and V resulted in severe disruption of elastin fibers, and this cathepsin effect could be blocked by adding cystatin C to the incubation system.


CONCLUSIONS
Stenotic aortic valves show increased expression and activity of elastolytic cathepsins S, K, and V. These cathepsins may accelerate the destruction of aortic valvular extracellular matrix, so promoting the progression of aortic stenosis.
Helske
Satu
S
Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Syväranta
Suvi
S
Lindstedt
Ken A
KA
Lappalainen
Jani
J
Oörni
Katariina
K
Mäyränpää
Mikko I
MI
Lommi
Jyri
J
Turto
Heikki
H
Werkkala
Kalervo
K
Kupari
Markku
M
Kovanen
Petri T
PT
D001021:Aortic Valve / Q000378:metabolism*; D001024:Aortic Valve Stenosis / Q000378:metabolism*; D016022:Case-Control Studies; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004549:Elastin / Q000378:metabolism; D005470:Fluorometry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D012333:RNA, Messenger / Q000378:metabolism
C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D012333:RNA, Messenger; D004549:Elastin; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K; C117627:CTSV protein, human