STAT1调控血管平滑肌细胞表型在动脉粥样硬化中的作用和机制研究

Vascular smooth muscle cells (VSMCs) are highly specialized cells with profound plasticity. VSMCs can switch from contractile phonotype to synthetic phenotype in response to environmental cues. Phenotypic switch of VSMCs has been demonstrated to be involved in atherosclerosis. However, the molecular mechanisms underlying VSMC phenotypic transition are not fully understood. To study the role of transcription factor STAT1 in VSMCs, we generated SMC-specific deficiency of STAT1 by crossing Sm22α Cre line onto STAT floxed allele. RNA-seq reveals that SMC contractile genes are upregulated in STAT1 -/- VSMCs, which is accompanied by downregulation of several Kruppel-like factor (KLF) genes. Moreover, SMC conditional knockout of STAT1 is able to attenuate severe vascular inflammation and atherosclerosis in ApoE mice with a point mutation in platelet-derived growth factor receptor beta (PDGFRβ), which increases the basal receptor activity. The aim of this proposal is to study the function of STAT1 in SMC phenotype and its role in atherogenesis, and to clarify the molecular mechanism of SMC phenotypic transition and provide new therapeutic target and interventions for vascular diseases including atherosclerosis.

平滑肌细胞是一种高度特化的细胞, 同时具有可塑性。平滑肌细胞可发生可逆的、收缩表型向合成表型的转换，研究显示平滑肌细胞表型转化参与动脉粥样硬化的发生。平滑肌细胞表型转换的分子机制尚不清楚。课题组研发出了平滑肌细胞选择性STAT1基因敲除小鼠（STAT1cKO）。STAT1cKO小鼠血管平滑肌细胞转录组测序（RNA-seq）揭示，STAT1-/-平滑肌细胞分化基因表达升高，细胞增殖活力下降，并伴有多个Kruppel样转录因子表达下调。平滑肌细胞STAT1敲除可减轻PDGFRβ活化引发的动脉粥样硬化。STAT1本身是否调控平滑肌细胞表型，并在动脉粥样硬化发生和发展中发挥作用值得探讨。本课题拟运用平滑肌细胞STAT1特异敲除小鼠模型，研究STAT1对平滑肌细胞表型调控的作用和机制，以及对动脉粥样硬化的影响，以期阐明平滑肌细胞表型转换的新机制，为寻找新的动脉粥样硬化药物靶点和治疗手段提供理论指导。

心肌肥厚（Cardiac hypertrophy）以心室壁增厚为主要特征，是心脏对心室后负荷增加的一种代偿反应。然而长此以往心肌肥厚最终会导致心肌衰竭、心律失常和心肌缺血等疾病的发生。心肌肥厚的病因和发病机制目前尚不完全清楚。本研究利用心脏特异性Stat1基因敲除小鼠，结合细胞生物学、分子生物学和形态、功能学手段，对Stat1基因在心肌肥厚中作用进行了系统地研究。我们发现Stat1通过下调心肌肥厚标志物（ANP、BNP、α-MHC）和纤维化标志物（Collagen I、Collagen III、Fibronectin）mRNA水平，并通过Ucp2/P-Drp1通路促进心肌细胞线粒体分裂,增加心肌细胞线粒体ATP生成，抑制心肌肥厚。同时Stat1和Stat3在心肌细胞肥厚中的作用是分别独立的。Stat1有望成为治疗心肌肥厚的潜在治疗靶点。本研究阐明了转录因子Stat1与心肌肥厚发生之间关系，为开发新型心肌肥厚治疗药物奠定了基础。项目资助发表英文研究论文三篇，英文综述一篇，英文修回论文一篇。培养博士研究生一名，硕士研究生三名。项目投入经费57万元，支出经费56.1864万元，结余0.8136万元，各项支出与预算一致,结余资金将用于项目后续研究。