IL-6/STAT3信号通路在主动脉瓣成骨钙化中的作用及机制研究

Calcific aortic valve disease has become the most common heart valve disease worldwide；however， the cellular and molecular mechanisms remain unclear. Increasing studies showed that inflammation plays a critical role in this pathological process. In one of our previous studies, we found plenty of IL-6 in calcific aortic valve, and that IL-6 could induce the osteoblastic differentiation of aortic valve interstitial cells(AVICs). We identified the higher expression of STAT3 and phosphorylated STAT3 in calcific AVICs. JAK2/STAT3 is a classic downstream signal pathway of IL-6， and therefore, we presume that IL-6 induce the osteoblastic differentiation of AVICs though the JAK2/STAT3 pathway, and eventually, leading the calcification of aortic valve. We will study the effects of IL-6 in vitro and vivo model，siRNA and knockdown rats will also been used in our study.Our study will further confirm the correction of inflammation and valve calcification, and will provide more evidences to illustrate the molecular mechanism. In addition, our study will also show new clinical molecular targets for the prevention and treatment of this disease.

钙化性主动脉瓣疾病已成为欧美国家最普遍的心脏瓣膜病，目前其发病机制尚不明确。近期大量研究表明炎症在其发病机理中扮演重要角色。我们前期工作发现：钙化的主动脉瓣膜中浸润大量IL-6，且其可促进主动脉瓣间质细胞成骨样分化。此外，在钙化瓣膜来源的间质细胞中IL-6经典下游信号 蛋白STAT3表达及其磷酸化水平均显著增强。因而我们推测：IL-6激活STAT3信号通路后诱导主动脉瓣间质细胞成骨样分化，并最终导致主动脉瓣钙化。本研究将通过构建小鼠主动脉瓣钙化模型及体外瓣膜间质细胞钙化模型，检测IL-6对瓣膜间质细胞成骨样分化及成钙能力的影响，并利用STAT3 siRNA及STAT3敲基因小鼠模型，阐释此促进作用由STAT3介导完成。本研究结果将进一步证实炎症和瓣膜钙化的相关性，为阐明主动脉瓣钙化发病机制提供新的实验依据，为临床防治提供新靶点。