经典Wnt/β-catenin通路激活致妊娠期糖尿病子代心肌肥厚的研究

Prevalence rate of gestational diabetes mellitus (GDM)-induced cardiac hypertrophy is rapidly increasing, but the underlying mechanisms remain unclear. Our previous studies have confirmed canonical Wnt/β-catenin pathway is involved in the cardiac development in fetus and the overexpression of β-catenin results in cardiac hypertrophy in fetus; the continuous activation of β-catenin/Tcf7l2 pathway leads to cardiomyopathy in adult diabetic mice. Preliminary data have shown that the expression of β-catenin and Tcf7l2 is up-regulated in the GDM fetal hearts. Therefore, the hypothesis of the project is that GDM activates cardiac canonical Wnt/β-catenin/Tcf7l2 pathway, resulting in cardiac hypertrophy in offspring. Chromatin remodeling complex Brg1 can directly bind to β-catenin, promoting its target gene transcription. Consistent with the up-regulation of β-catenin, GDM also increases the expression of Brg1 in the offspring. Therefore, Brg1 plays an important role in the regulation of cardiac hypertrophy induced by β-catenin activation in GDM offspring. To prove the above hypothesis, our project will utilize the fetal, newborn and adult offspring from pregnant control, β-catenin knockout or overexpression transgenic diabetic mice to test the role of Wnt/β-catenin/Tcf7l2 pathway over-activation in GDM-induced cardiac hypertrophy in the offspring and explore the nuclear mechanism in depth, providing new molecular targets for the prevention of cardiac hypertrophy in GDM offspring.

妊娠期糖尿病（GDM）子代心肌肥厚患病率增加但机制未阐明。项目组前期研究显示经典Wnt/β-catenin通路调控心脏胚胎发育，过表达β-catenin导致胚胎心脏肥大；糖尿病时β-catenin/Tcf7l2通路持续活化引起成年小鼠心肌损伤；预实验发现GDM子代胎鼠心脏β-catenin、Tcf7l2表达上调。由此推测GDM激活子代心脏经典β-catenin/Tcf7l2通路导致心肌肥厚。染色质重塑复合物Brg1 能与β-catenin结合促进靶基因转录，GDM子代胎鼠心肌Brg1表达与β-catenin趋势一致，因此Brg1可能调控β-catenin活化致GDM子代心肌肥厚的作用。为证实上述推测，本研究利用β-catenin过表达或敲除的糖尿病孕鼠，以不同周龄子代小鼠为对象，明确Wnt/β-catenin/Tcf7l2过度活化在GDM致子代心肌肥厚中的作用及机制，为该疾病防治提供新策略

随着人们生活水平的提升，妊娠期糖尿病（GDM）的发病率越来越高。研究报道GDM子代患心血管疾病的风险显著增加，但机制不清。本项目以“GDM持续激活心脏Wnt/β-catenin信号通路导致子代心肌肥厚、心功能障碍”为核心科学问题，利用孕前和孕期高脂饮食饲养建立GDM小鼠模型，动态观察GDM子代从胚胎期到成年期的不同阶段，明确心肌肥厚、心功能障碍发生发展过程；随后，通过RNA-Seq筛发现GDM子代心肌中Wnt/β-catenin持续活化，β-catenin表达且入核增多；进一步利用β-catenin敲除、过表达的基因工程小鼠构建GDM模型，结果显示β-catenin表达降低GDM子代心肌肥厚改善；反之，β-catenin表达增高则子代心肌肥厚明显加重，提示GDM诱导的Wnt/β-catenin持续活化是导致子代心肌肥厚、功能异常的重要信号通路。创新性试用二肽激肽酶4抑制剂（DPP4i）沙格列汀干预GDM，结果显示沙格列汀干预GDM改善子代心肌肥厚的作用优于NPH和二甲双胍，这一作用是通过部分性抑制Wnt/β-catenin通路实现。本项目系列研究结果为GDM子代心肌肥厚的防治提供新的机制及分子靶标。