心肌肥厚易感心律失常的新机制：STAT3/miR-27a/Hoxa10轴调控心肌电重构

Cardiac hypertrophy is a common pathological process of various cardiovascular diseases, accompanied with electrical remodeling which may result in lethal arrhythmia. However, its molecular mechanism remains largely elusive. Our previous study demonstrates that KCND2/KCND3 and KCNJ2 channels may be regulated by Hoxa10. It suggests that Hoxa10 may be a new regulator of heart rhythm. Thus, the upstream and downstream pathway is intensely required to be manifested. In present study, we hypothesize that in cardiac hypertrophy,STAT3/miR-27a/Hoxa10 axis inhibits Kv4.2/Kv4.3/Ito and Kir2.1/IK1 channels through transcriptional regulation of KCND2/KCND3 and KCNJ2, which leads to APD prolongation, membrane potential depolarization and arrhythmia. We aim to verify the involvement of STAT3/miR-27a/Hoxa10 axis in hypertrophic electrical remodeling and its molecular mechanism using patch-clamp, ChIP, luciferase reporter assay etc. We hope to reveal Hoxa10 as a new therapeutic target in cardiac hypertrophy treatment. It may hold a promise for the treatment of cardiac hypertrophy-related arrhythmia.

心肌肥厚是多种心血管疾病共有的病理过程，其因电重构常伴随心律失常的发生，甚至引发猝死，但其深层分子机制仍不清楚。在前期研究中我们发现转录因子Hoxa10对KCND2/KCND3和KCNJ2等通道具有调控作用，提示Hoxa10可能是心律失常发生新的调控因子，但需进一步验证，此外其上下游信号通路也需阐明。在本项目中我们提出假设：心肌肥厚时STAT3/miR-27a/Hoxa10通路通过转录调控KCND2/KCND3和KCNJ2离子通道的表达，抑制Kv4.2/Kv4.3/Ito和Kir2.1/IK1，导致心肌APD延长和膜电位除极化，促发心律失常。本研究拟运用膜片钳、ChIP等技术验证STAT3/miR-27a/Hoxa10轴是否参与了肥厚心肌电重构过程并阐明其分子机制，探讨Hoxa10能否成为防治心肌肥厚时心律失常发生的新靶点，对于临床上心肌肥厚易感心律失常的治疗具有积极意义。

心肌肥厚是各种心血管疾病常见的病理过程，常伴有结构和电重构，甚至可导致心源性猝死。然而，其分子机制在很大程度上仍不十分清楚。在此，我们用血管紧张素II(Ang II)诱导心肌细胞肥大，发现miR-27A-3p和肥大相关基因表达上调。进一步的研究表明miR-27a-3p抑制剂可以减轻心肌肥大和电重构。荧光素酶分析证实miR-27a-3p通过靶向Hoxa10的3‘非编码区，可以在转录水平调控下游基因Hoxa10的表达。同时，AngⅡ处理的心肌细胞中Hoxa10蛋白的表达明显降低。此外，Hoxa10的过表达可以逆转AngⅡ诱导的心肌细胞肥大和电重构。最后，我们发现Hoxa10正向调控钾通道蛋白Kv4.3的表达，该蛋白在肥大心肌细胞中也被下调。综上所述，我们的结果表明miR27a-3p/Hoxa10/Kv4.3轴是AngⅡ诱导心肌细胞肥大的新机制，为临床防治心肌肥厚和心力衰竭提供了新的靶点。