转录因子SOX9促进血管平滑肌细胞向软骨样表型转化从而加剧血管钙化的作用及机制

血管钙化是动脉粥样硬化的标志，其发生的关键步骤是血管平滑肌细胞（VSMC）向软骨样表型转化。该转化为收缩→合成表型的特殊形式，但其调控机制未明。SOX家族转录因子在软骨细胞分化中发挥重要作用，但其在VSMC向软骨细胞样转化中的作用尚无相关研究。申请人检测了TGF-β诱导VSMC的钙化沉积及差异表达基因，发现SOX9增高显著。体外沉默SOX9可减轻TGF-β刺激后的钙化沉积。VSMC特异性SOX9敲除小鼠的血管钙化模型中，颈动脉钙化范围明显减小。进一步在过表达SOX9的VSMC中寻找差异表达基因，发现Matn1、CDKN1ɑ及CDK4的表达明显升高。本研究拟明确：1）SOX9促进VSMC向软骨细胞样表型转化从而导致血管钙化的作用；2）SOX9通过上调其下游靶基因Matn1、CDKN1ɑ和CDK4的表达而促进血管钙化的机制；3）血清中SOX9水平是否可作为血管钙化预警及治疗的新靶点。

Vascular calcification is an important feature of atherosclerosis. The key step in the pathogenesis of vascular calcification is the transformation of vascular smooth muscle cells into chondrocyte-like phenotypes, which is a special form of synthetic phenotype, dedifferentiated from contractile phenotype. But its underlying molecular mechanism is unclear. SOX family of transcriptional factors play an important role in the chondrocyte differentiation, but its role in the transformation of vascular smooth muscle cells to chondrocyte-like cells has not been studied. This study examined the calcific deposition and differentially expressed genes of rat aortic smooth muscle cells induced by TGF-β, and found that the expression of most members of the SOX family has changed, with SOX9 increased significantly. While silencing SOX9 in vitro can reduce calcific deposition after TGF-β stimulation. Compared with wild-type mice, in the vascular calcification model of smooth muscle cell-specific SOX9 knockout mice, the extent of carotid calcification was significantly reduced. Furthermore, in smooth muscle cells overexpressing SOX9, we found multiple differentially expressed genes and of them Matrilin1, CDKN1ɑ and CDK4 were significantly increased. Therefore, this study plans to clarify: 1) the role of SOX9 in promotion of vascular smooth muscle cells into chondrocyte-like phenotype and in the subsequent process of vascular calcification; 2) the mechanism of SOX9-induced vascular calcification by up-regulation of the expression of its downstream target genes Matrillin1, CDKN1ɑ and CDK4; 3) Whether the serum SOX9 level can be used as a new index for early-prediction and therapeutic target of vascular calcification.