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

Aims Aortic stenosis (AS) is characterized by extensive remodellingof the valves, including infiltration of inflammatory cells,extracellular matrix degradation, and fibrosis. The molecularmechanisms behind this adverse remodelling have remained obscure.In this article, we study whether cathepsin G, an angiotensinII (Ang II)-forming elastolytic enzyme, contributes to progressionof AS. Methods and results Stenotic aortic valves (n=86) and controlvalves (n=17) were analysed for cathepsin G, transforming growthfactor-ß1 (TGF-ß1), and collagens I andIII with RT–PCR and immunohistochemistry. Valvular collagen/elastinratio 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) withthe expression levels of TGF-ß1 and collagens I andIII. TGF-ß1 was also present in mast cell-rich areasand cathepsin G induced losartan-sensitive TGF-ß1expression in cultured fibroblasts. Collagen/elastin ratio wasincreased in stenotic valves (P<0.001) and correlated positivelywith smoking (P=0.02). Nicotine in cigarette smoke activatedmast cells and induced TGF-ß1 expression in culturedfibroblasts. Fragmented elastin was observed in stenotic valvescontaining activated cathepsin G-secreting mast cells and innormal valves treated with cathepsin G. Conclusion In stenotic aortic valves, mast cell-derived cathepsinG may cause adverse valve remodelling and AS progression.