钙化性主动脉瓣膜病中FSTL3促主动脉瓣膜间质细胞钙化的机制研究

主动脉瓣钙化是多种心脏疾病的危险因素之一，但其发病机制未清。本研究前期发现：主动脉瓣膜钙化病人中FSTL3分泌升高，与年龄呈正相关性，而钙化瓣膜中瓣膜间质细胞表达量显著上升。FSTL3可促进瓣膜间质细胞钙化程度，而其表达受Sirt1调控。其结合蛋白为Activin A及MSTN，测序分析提示FSTL3调控SOX9等基因并对HIF-1α具调控作用。这提示FSTL3通过多重调控作用促进瓣膜间质细胞钙化过程是主动脉瓣膜钙化进展的重要机制。因此，本研究将探讨：1）Sirt1调控FSTL3表达的机制；2）FSTL3与其结合蛋白对瓣膜钙化的调控机制；3）FSTL3对SOX9-RUNX2轴的调控机制； 4）FSTL3对HIF-1α通路的调控机制；5）在体研究FSTL3对主动脉瓣膜钙化进展的调控机制。通过以上研究以期阐释FSTL3对主动脉瓣膜钙化发展的相关机制，为在体干预治疗主动脉瓣膜钙化提供科学依据。

Calcific aortic valve is one of a variety of risk factors for heart diseases, but the pathogenesis is not clear. Now we found that: the expression of FSTL3 is increased in serum and valve interstitial cells of valve tissues of aortic valve calcification, and positive related with age. Sirt1 regulated the expression of FSTL3 in valve interstitial cells. Moreover, FSTL3 promoted the calcification of valve interstitial cells and bind with Activin A and MSTN. The RNA-sequencing assay showed that FSTL3 regulated some genes (such as SOX9) expression and HIF-1α activation. These results hint that FSTL3 regulated valvular interstitial cells calcification process via multiple signaling pathways, which is an important mechanism of aortic valve calcification progression. Therefore, this study will examine: 1) the expression of FSTL3 is regulated via Sirt1; 2) FSTL3 bind with proteins to regulated calcification; 3) the mechanism of SOX9-RUNX2 axis was regulated via FSTL3; 4); the mechanism of FSTL3 regulated HIF-1α signaling pathway; 5) in vivo, the aortic valve calcification progress of FSTL3 regulatory mechanisms. Through these studies to explain the mechanisms of aortic valve calcification regulated by FSTL3, which provide a scientific basis and experimental basis for therapeutic intervention in vivo aortic valve calcification.