锌指蛋白ZBTB20对血管平滑肌细胞分化及表型转换的调控作用

Abnormal differentiation and phenotypic switching of vascular smooth muscle cells (VSMC) is the pathogenesis of atherosclerosis and other cardiovascular disease. Transcription regulation of gene expression plays a key role in the differentiation and phenotypic switching of VSMC. Zinc finger protein ZBTB20 is independently cloned by our group, and first reported on the international, which is highly expressed in VSMC. In order to further understand the biology function of ZBTB20 in vessel, we used the Cre/loxp technology to establish a smooth muscle specific ZBTB20 knockout mice (SMCZB20KO) model, and found obvious abnormal vascular structures in the mice, and significantly lower diastolic blood pressure was observed in SMCZB20KO mice. Further tests revealed vascular smooth muscle cell differentiation in SMCZB20KO mice appeared apparently abnormal, and vasoconstrictor function declined obviously. These preliminary results suggest ZBTB20 plays an important role in the differentiation and function of VSMC. In the present study, we further analysis the role of ZBTB20 in the differentiation and phenotypic switching of VSMC and clarify its mechanism. We want to provide a new experimental basis for the deep understanding of the molecular mechanism of differentiation and phenotypic switching of VSMC.

血管平滑肌细胞(VSMC)的分化异常和表型转换是动脉粥样硬化等多种心血管病的发病基础，VSMC基因表达的转录水平调节在其分化和表型转换中起着关键作用。锌指蛋白ZBTB20，是申请人所在课题组自主克隆、并在国际上率先报道的新转录因子，在VSMC中高表达。为进一步了解ZBTB20 在血管中的生物学功能，我们利用Cre/loxp 技术建立了平滑肌特异性ZBTB20 敲除（SMCZB20KO）小鼠模型，发现该模型小鼠血管结构异常，舒张压明显降低。进一步检测显示SMCZB20KO小鼠VSMC分化出现明显异常，血管收缩功能明显下降。这些前期结果提示ZBTB20在VSMC的分化和功能中起着重要的作用。本课题拟在此基础上，深入分析ZBTB20在VSMC分化和表型转换中的作用及其机理，探索转录因子对VSMC的分化的网络化调控，为深入理解调控VSMC分化和表型转换的分子机制提供新的实验依据。

血管平滑肌细胞(VSMC)的分化异常和表型转换是动脉粥样硬化等多种心血管病的发病基础，VSMC基因表达的转录水平调节在其分化和表型转换中起着关键作用。锌指蛋白ZBTB20，是申请人所在课题组自主克隆、并在国际上率先报道的新转录因子，在VSMC中高表达。为进一步了解ZBTB20 在血管中的生物学功能，我们利用Cre/loxp 技术建立了平滑肌特异性ZBTB20 敲除（SMCZB20KO）小鼠模型，发现该模型小鼠血管结构异常，胸主动脉对高钾和苯肾上腺素引起的血管收缩幅度明显减弱，舒张压明显降低。进一步检测显示SMCZB20KO 小鼠VSMC中分化的标志基因SM22a表达明显降低，在他莫昔芬诱导平滑肌细胞ZBTB20敲除小鼠模型中也观察到了一致的结果。在培养的平滑肌细胞株中，经SMDS诱导分化后，ZBTB20与SM22a蛋白表达水平明显升高，与小鼠平滑肌细胞中敲除ZBTB20后SM22a表达水平显著下降的结果相互验证。在自发性高血压SHR大鼠主动脉平滑肌细胞ZBTB20的表达明显降低，进一步提示ZBTB20在平滑肌细胞的增殖和分化中可能起着重要作用出现明显异常。这些结果为完善ZBTB20的生物学功能尤其在心血管系统的功能提供了重要依据。