on May 25, 2006
Published online before print May 25, 2006, doi: 10.1161/01.ATV.0000228824.01604.63
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Submitted on December 29, 2005
Accepted on May 8, 2006
Increased Expression of Elastolytic Cathepsins S, K, and V and Their Inhibitor Cystatin C in Stenotic Aortic Valves
Satu Helske ;
From the Wihuri Research Institute (S.H., S.S., K.A.L., J.L., K.O., M.I.M., P.T.K.), Helsinki, Finland; and Division of Cardiology, Department of Medicine (J.L., H.T., M.K.) and Division of Cardiothoracic Surgery, Department of Surgery (K.W.), Helsinki University Central Hospital, Helsinki, Finland.
* To whom correspondence should be addressed. E-mail: petri.kovanen{at}wri.fi.
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.
Methods and 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.
Key words: aortic stenosis • cathepsin • cystatin C • elastin • heart valves
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