转录调控因子SOX4在病理性心肌肥厚中的作用及机制研究

病理性心肌肥厚可进行性发展为心力衰竭，因此抑制病理性心肌肥厚的发展具有重要意义。SOX4作为SOX转录因子家族成员的一员，参与调控多个组织的生长发育，但对病理性心肌肥厚的影响尚不清楚。我们的前期结果显示心肌肥厚小鼠心肌组织中SOX4蛋白表达上调，通过抑制原代心肌细胞中SOX4表达可逆转Ang Ⅱ诱导的细胞肥大及ROS增多，此外SOX4可与SIRT3启动子结合调控其转录活性。基于SIRT3可通过调节抗氧化作用及线粒体功能发挥心肌保护作用，我们推测：心肌肥厚过程中表达上调的SOX4结合SIRT3启动子抑制其转录，进而影响下游抗氧化基因的表达及线粒体功能，促进病理性心肌肥厚的发生。为了证实这一推测，我们将复制小鼠心肌肥厚模型和心肌细胞肥大模型，通过多种分子生物学技术阐明SOX4在心肌肥厚中的作用，并探究通过SOX4这一新靶点治疗心肌肥厚发展的方法，为心肌肥厚的治疗提供坚实的实验基础。

As pathological cardiac hypertrophy can progressively develop into cardiac failure, it is of great significance to inhibit the development of pathological cardiac hypertrophy. SOX4, a member of SOX transcription factor family, plays a part in regulating the growth and development of numbers of tissues. However, its effects on pathological cardiac hypertrophy still remain unclear. According to our early studies: SOX4 expression in myocardial tissues of mice with cardiac hypertrophy is significantly up-regulated; cardiomyocyte hypertrophy and ROS increase induced by Ang II can be reversed by inhibiting SOX4 expression in neonatal rat cardiomyocytes. Besides, we also discovered that SOX4 can bind with SIRT3 promoter to regulate its transcriptional activity. In view of the fact that SIRT3 plays the role of cardioprotective effects by regulating antioxidation and mitochondrial function, we conjecture: SOX4, whose expression is up-regulated during the cardiac hypertrophy, binds with SIRT3 promoter to inhibit its transcription, thus affects the expression of downstream antioxidation genes and mitochondrial functions, and then facilitates the development of pathological cardiac hypertrophy. To verify such conjecture, we’ll copy mice cardiac hypertrophy model and cardiomyocyte hypertrophy model to make clear the role that SOX4 plays in cardiac hypertrophy by adopting various molecular biological technologies, and develop novel therapy for inhibiting cardiac hypertrophy development through targeting SOX4. In this way, we expect to lay a solid experimental foundation for the treatment of cardiac hypertrophy.