LncRNA H19通过IGF2/IGF2R信号通路促进慢性心力衰竭心肌重构的作用 机制研究

Myocardial remodeling is the most basic pathological process of chronic heart failure (CHF) in which the activation of Insulin-like growth factor 2 and Insulin-like growth factor 2 receptor (IGF2/IGF2R)signaling pathways plays an important role. LncRNA H19 is one of the earliest identified imprinted genes, belonging to the same genetic imprinting with IGF2. The expression of H19 is strongly induced during embryogenesis and downregulated after birth, except in adult skeletal muscle and heart.Our pilot study has identified that a significant increase of the expression of H19 , in both CHF rats and pathologic hypertrophy myocardial cell model, as a positive regulator of IGF2. Our further study also found that the expression of H19 in plasma was significantly elevated in both CHF rats and patients. Accordingly, we hypothesized that in the process of the cardiomyocyte injury, up-regulated H19 could promote the activation of IGF2/IGF2R signaling pathways, and subsequently cause myocardial remodeling in the development of CHF. To the best of our knowledge, it could be the first further investigation of the mechanism by which H19 promotes myocardial remodeling by regulating IGF2/IGF2R signaling pathways in molecular, cardiomyocyte and rat models in the present study. Moreover, a follow-up study would be performed to evaluate the correlation between H19 and CHF. Our study might reveal new pathological mechanism of myocardial remodeling, and provide a new insight into diagnosis and treatment for CHF.

心肌重构是各种心血管疾病进展为慢性心力衰竭(CHF)的最基本病理过程，其中胰岛素样生长因子2及其受体（IGF2/IGF2R）信号通路的激活起重要作用。LncRNA H19是最早被鉴定的印记基因之一，与IGF2隶属同一基因印记群。H19高表达于胚胎发育期，出生后仅在心肌和骨骼肌中有一定表达。我们前期发现H19在CHF大鼠和细胞肥大模型中均升高，并正向调控IGF2表达；进一步研究发现CHF大鼠及患者血浆H19亦有升高。据此提出科学假说：心肌细胞损伤，H19表达增加，通过激活IGF2/IGF2R信号通路，促进心肌细胞重构，参与CHF发生发展。本项目将从分子、细胞和动物三个层次探索H19通过IGF2/IGF2R信号通路促进心肌重构的作用机制；并进一步探索血浆H19水平与CHF患者心功能变化及预后的相关性。本研究将从lncRNA H19这个新视点揭示心肌重构的机制，为CHF的诊治提供新的思路和靶点。

背景和目的：慢性心力衰竭是各种心血管疾病发展的终末阶段，也是最主要的死亡原因。心肌重构是心血管疾病发病率和病死率的独立危险因素，是导致各种心血管疾病发展为慢性心衰最重要的病理生理基础，探明心肌重构的具体机制对慢性心衰的防治显得尤为迫切。长链非编码RNA（LncRNA）是一系列参与各种疾病的调控分子，越来越多的研究表明其在心血管病中发挥了重要作用。本项目前期通过基因芯片技术筛选出lncRNA H19在慢性心衰发生时差异最为显著。H19是最早被发现的印记基因之一，出生后仅表达于心肌和骨骼肌中，广泛参与生长发育进程及肿瘤的发生发展。近年来研究表明H19可参与调控心肌细胞发育、凋亡和死亡等。本项目旨在探索H19在慢性心衰病理性重构中的功能和可能机制，为慢性心衰的诊治提供新的方向和靶点。.方法和结果：1.H19在CHF大鼠和细胞肥大模型中表达均升高。2.我们在原代心肌细胞中干预H19表达发现，过表达H19能显著抑制ISO诱导的病理性心肌肥大，抑制H19表达能够促进病理心肌肥大。3.心肌细胞中lncRNA H19可以反向调节IGF2的表达。干扰IGF2/IGF2R信号通路可以抑制Gaq/PKC-α的磷酸化，从而减轻沉默H19引起的病理性心肌肥大；激活IGF2/IGF2R信号通路，可增加Gaq/PKC-α的磷酸化，从而减弱H19对病理性心肌肥大的抑制作用。4.我们的体内研究首次发现H19能显著减少心衰小鼠心重与体重比、心重与胫骨长比、LVsd和LVPWd，减轻心肌重构，显著改善心功能。5.发明并制备了一种诊断敏感性和特异性较高的包括血清lncRNA H19的慢性心力衰竭患者早期诊断的制剂。.结论：慢性心衰时 LncRNA H19通过调控IGF2/IGF2R信号通路，进而减少Gaq/PKC-α的磷酸化，抑制病理性心肌重构，改善心功能。我们的研究将为心肌重构及慢性心衰提供新的诊治靶点。