Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification.
Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification.
复制标题
DOI：
10.1161/atvbaha.115.306091
复制
发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Lincoln J
中科院分区：
文献类型：
--
作者：
Huk DJ;Austin BF;Horne TE;Hinton RB;Ray WC;Heistad DD;Lincoln J
包括钙化在内的主动脉瓣疾病影响超过2%的人口，是由多种风险因素（包括基因突变、环境和生物力学）之间的复杂相互作用引起的。目前，除了手术外，没有其他有效的治疗方法，这是由于对这种疾病的机制了解有限。先前的研究表明，主动脉瓣尖内的瓣膜间质细胞（VIC）分化为成骨细胞样细胞和存款骨样基质，导致瓣叶硬化和钙化性主动脉瓣狭窄。然而，促进VIC病理表型的机制尚不清楚。使用体外和体内工具与小鼠，猪和人体组织的组合，我们表明，在VIC，减少Sox 9的表达和核定位之前发生钙化。在体外，Sox 9核输出和钙化结节形成被瓣膜内皮细胞（VEC）阻止。而在体内，内皮中TGFβ1的缺失导致Sox 9表达减少和钙化性主动脉瓣疾病。总之，这些发现表明，VIC中Sox 9的核定位减少是钙化的早期指标，因此，防止核输出的药理学靶向可以作为预防钙化和狭窄的新治疗工具。
Aortic valve disease, including calcification affects more than 2% of the human population and is caused by complex interactions between multiple risk factors including genetic mutations, the environment and biomechanics. At present, there are no effective treatments other than surgery and this is due to the limited understanding of the mechanisms that underlie the condition. Previous work has shown that valve interstitial cells (VICs) within the aortic valve cusps differentiate towards an osteoblast-like cell and deposit bone-like matrix that leads to leaflet stiffening and calcific aortic valve stenosis. However the mechanisms that promote pathological phenotypes in VICs are unknown. Using a combination of in vitro and in vivo tools with mouse, porcine and human tissue, we show that in VICs, reduced Sox9 expression and nuclear localization precedes the onset of calcification. In vitro, Sox9 nuclear export and calcific nodule formation is prevented by valve endothelial cells (VECs). While in vivo, loss of Tgfβ1 in the endothelium leads to reduced Sox9 expression and calcific aortic valve disease. Together, these findings suggest that reduced nuclear localization of Sox9 in VICs is an early indicator of calcification and therefore pharmacological targeting to prevent nuclear export could serve as a novel therapeutic tool in the prevention of calcification and stenosis.