蓬乱蛋白在高糖刺激诱导心肌肥大中的作用和机制研究

Long term hyperglycemia leads to cardiac hypertrophy. Although Wnt signaling pathway plays a pivotal role in glucose metabolism and myocardial hypertrophy, it’s still unclear whether and how it works in high blood glucose induced cardiac hypertrophy. Our preliminary data showed a significant hypertrophied response to streptozotocin (STZ) in type 1 diabetic mouse model. Additionally, we found a notable upregulation of dishevelled (Dvl1), which is the hub of Wnt signaling pathway. Inhibition of Dvl1 abrogated the upregulation of c-Myc, a target gene of Wnt/β-catenin pathway, and consequently mediated the cardiac hypertrophy induced by high glucose stimulation. Thus, we hypothesize that Dvl1 acts as a key molecule promoting the upregulation of c-Myc and the resultant cardiac hypertrophy. In this project, we established global Dvl1 deficient model to explore the role of Dvl1 in the hyperglycemia-induced cardiac hypertrophic response in STZ treated-Dvl1 gene knockout mice or siRNA transduced-cardiomyocytes. Furthermore, we will illustrate the underlying mechanism by which hyperglycemia regulates the expression of Dvl1. The present study promisingly provides an underlying rationale and new therapeutic approach for the clinical prevention of hyperglycemia-induced myocardial injury

长期高糖刺激可致心肌肥大，虽然Wnt通路介导了糖代谢和心肌肥大过程，但是它在高糖刺激诱导心肌肥大中的作用尚不清楚。我们前期在链脲佐菌素（STZ）诱导的1型糖尿病小鼠中检测到了显著的心肌肥大，并伴Wnt通路核心分子——蓬乱蛋白（Dvl1）显著上调；且抑制Dvl1表达可降低高糖刺激引起的Wnt/β-catenin通路目标基因c-Myc的表达和心肌肥大反应。因此，我们推断Dvl1是促进c-Myc基因上调从而介导高血糖所致心肌肥大的关键信号蛋白。本项目将在前期发现的基础上，通过基因敲除或siRNA在体内、外实验中构建Dvl1功能缺失模型，以在体STZ诱导和离体高糖刺激探讨Dv11在介导高糖刺激诱发心肌肥大中的作用和相关信号通路；并阐述高糖刺激调控Dvl1表达的分子机制，为临床高血糖症所致心肌损害的防治提供新的理论依据和治疗靶点

心室重塑包括心肌肥大和心脏纤维化等病理性改变，目前仍无有效的针对病理性心室重塑的治疗手段问世。ACKR4是非经典趋化因子受体(ACKR)中的一员，前期研究发现ACKR4可清除趋化因子：CCL19 、CCL21 、CCL25，目前关于ACKR4心肌梗死后心室重塑的作用仍然未知。对此我们展开了研究，我们首先检测了心梗后不同时间点ACKR4的表达情况，发现心梗后第7天心脏中ACKR4的表达显著增加。接下来，我们使用ACKR4-KO小鼠，进行MI造模。意外的发现ACKR4并不调节心梗后的心肌肥大，但是我们发现与WT小鼠相比，心梗后ACKR4-KO小鼠的心脏纤维化及EndMT得到了明显的改善。进一步研究发现，ACKR4可通过激活p38-MAPK/NF-κB信号通路，从而促进IL-6的产生。心脏成纤维细胞通过旁分泌IL-6, 作用于内皮细胞促进其向间充质的转化，从而促进纤维化。此研究发现ACKR4可调节心梗后的心脏纤维化，建立了心梗后心脏纤维化和IL-6的内在联系，为干预心梗后的心室重塑提供了靶点。