Helske Satu, Syväranta Suvi, Kupari Markku, Lappalainen Jani, Laine Mika, Lommi Jyri, Turto Heikki, Mäyränpää Mikko, Werkkala Kalervo, Kovanen Petri T, Lindstedt Ken A
Wihuri Research Institute, Helsinki, Finland.
Eur Heart J. 2006 Jun;27(12):1495-504. doi: 10.1093/eurheartj/ehi706. Epub 2006 Jan 9.
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.
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.
In stenotic aortic valves, mast cell-derived cathepsin G may cause adverse valve remodelling and AS progression.
主动脉瓣狭窄（AS）的特征是瓣膜广泛重塑，包括炎性细胞浸润、细胞外基质降解和纤维化。这种不良重塑背后的分子机制仍不清楚。在本文中，我们研究组织蛋白酶G（一种生成血管紧张素II（Ang II）的弹性蛋白酶）是否促进AS的进展。
采用逆转录聚合酶链反应（RT-PCR）和免疫组织化学方法分析86个狭窄主动脉瓣和17个对照瓣膜中的组织蛋白酶G、转化生长因子-β1（TGF-β1）以及I型和III型胶原蛋白。通过组织化学定量瓣膜胶原/弹性蛋白比率。在狭窄瓣膜中，组织蛋白酶G存在于肥大细胞中且表达增加（P<0.001），其与TGF-β1以及I型和III型胶原蛋白的表达水平呈正相关（P<0.001）。TGF-β1也存在于肥大细胞丰富的区域，并且组织蛋白酶G在培养的成纤维细胞中诱导氯沙坦敏感的TGF-β1表达。狭窄瓣膜中的胶原/弹性蛋白比率增加（P<0.001），并且与吸烟呈正相关（P = 0.02）。香烟烟雾中的尼古丁激活肥大细胞并在培养的成纤维细胞中诱导TGF-β1表达。在含有分泌组织蛋白酶G的活化肥大细胞的狭窄瓣膜以及用组织蛋白酶G处理的正常瓣膜中观察到弹性蛋白片段化。
在狭窄主动脉瓣中，肥大细胞衍生的组织蛋白酶G可能导致不良的瓣膜重塑和AS进展。
