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European Heart Journal Advance Access published online on January 9, 2006
European Heart Journal, doi:10.1093/eurheartj/ehi706
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European Heart Journal © The European Society of Cardiology 2005; all rights reserved
Received July 25, 2005
Revised December 2, 2005
Accepted December 8, 2005

Preclinical research

Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves

Satu Helske 1, Suvi Syväranta 1, Markku Kupari 2, Jani Lappalainen 1, Mika Laine 3, Jyri Lommi 2, Heikki Turto 2, Mikko Mäyränpää 1, Kalervo Werkkala 4, Petri T. Kovanen 1, and Ken A. Lindstedt 1 *

1 Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland
2 Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
3 Minerva Institute for Medical Research, Helsinki, Finland
4 Division of Cardiothoracic Surgery, Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland

* To whom correspondence should be addressed.
Ken A. Lindstedt, E-mail: ken.lindstedt{at}wri.fi


  Abstract

Aims 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.

Methods and results Stenotic aortic valves (n = 86) and control valves (n = 17) were analysed for cathepsin G, transforming growth factor-{beta}1 (TGF-{beta}1), 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-{beta}1 and collagens I and III. TGF-{beta}1 was also present in mast cell-rich areas and cathepsin G induced losartan-sensitive TGF-{beta}1 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-{beta}1 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.

Conclusion In stenotic aortic valves, mast cell-derived cathepsin G may cause adverse valve remodelling and AS progression.

Keywords: Angiotensin; Aortic stenosis; Cathepsin G; Elastin; Fibrosis; Mast cell.
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