YY1调控血管平滑肌细胞表型转化的作用及机制

Vascular smooth muscle cells (VSMC) are highly plastic and have the capacity to switch from contractile phenotype to synthetic phenotype, which result in enhanced proliferation, migration, and inflammation in the pathogenesis of several vascular diseases such as hypertension and atherosclerosis. VSMC differentiation is marked by the expression of a set of contractile proteins including smooth muscle alpha-actin (SMA), smooth muscle myosin heavy chain (SM-MHC), and SM22 alpha (SM22). In response to vascular injury, VSMC undergoes phenotypic modulation characterized by downregulation of VSMC contractile genes. It is demonstrated that this phenotypic modulation plays a pivotal role in vascular development and remodeling in diseases. However, the underlying molecular mechanisms of VSMC phenotypic modulation are not completely understood. By using the high-throughput overexpression screening technology, GFC-Transfection Array (from OriGene), we found transcription factor Yin-Yang 1 (YY1) suppressed VSMCs marker gene expression, and induced phenotypic modulation of the cells. Insights into the molecular mechanism of these effects are not presented. To address these concerns, molecular biological techniques, myograph system, and vascular injury model are used. We assume that YY1 inhibits myocardin expression and disturbs the interaction of myocardin/serum response factor (SRF) and SRF/CArG box, which result in the decreased VSMC gene transcription. This study may help to understand the molecular mechanisms of VSMC phenotypic modulation and provide new therapeutic strategy for vascular remodeling in diseases.

血管平滑肌细胞（VSMC）由收缩型向合成型的转变（表型转化）是高血压、动脉粥样硬化及血管成形术后再狭窄等血管重塑性疾病的共同病理学基础。阐明VSMC表型转化的调控机制，对防治血管重塑和逆转增殖性血管病变具有重要的意义。应用转录因子转染芯片技术（GFC-Transfection Array），我们筛选出转录因子YY1可显著抑制VSMC标志基因表达，诱导VSMC表型转化；但分子机制不明。本课题拟采用分子生物学技术、小血管肌动描记技术及血管损伤模型，从基因到功能，系统研究YY1调控VSMC标志基因的分子机制以及对血管舒缩功能的影响，旨在证明 "YY1通过抑制myocardin的表达、抑制myocardin/SRF相互作用、抑制SRF/CArG box结合而调节VSMC标志基因表达"的科学假设。该假设的证明，将丰富人们对VSMC表型转化调控机制的认识，并可能为防治血管重塑性疾病提供新的思路。

血管平滑肌细胞（VSMC）由收缩型向合成型的转变（表型转化）是高血压、动脉粥样硬化及血管成形术后再狭窄等血管重塑性疾病的共同病理学基础。阐明VSMC表型转化的调控机制，对防治血管重塑和逆转增殖性血管病变具有重要的意义。应用转录因子转染芯片技术（GFC-Transfection Array），我们筛选出转录因子YY1可显著抑制VSMC标志基因表达，诱导VSMC表型转化；但分子机制不明。本课题采用分子生物学技术及血管损伤模型，系统研究YY1调控VSMC标志基因的分子机制,发现YY1过表达可抑制VSMC标志基因如Tagln和Acta2的表达；相反YY1低表达可诱导VSMC标志基因表达。此外，YY1可负调节VSMC分化调控因子Myocardin的启动子活性和基因表达，该作用与其增强子上的三个YY1结合位点没有关系。再者,YY1可直接与Myocardin相互作用并影响Myocardin与SRF的相互作用。YY1还影响SRF和CArG box的结合。总之，该课题证明了“YY1通过抑制myocardin的表达、抑制myocardin/SRF相互作用、抑制SRF/CArG box结合而调节VSMC标志基因表达”的科学假设。不仅能丰富人们对VSMC表型转化调控机制的认识，并可能为防治血管重塑性疾病提供新的思路。