HDGF在应激性心肌病钙转运及心肌功能恢复中的作用及机制探究

Stress-induced cardiomyopathy results in temporary cardiac dysfunction, in which the disorder of calcium handling is one of the mechanisms. So far, the mechanism of SIC recovery remains unclear. Previously, we found that Hepatoma-derived growth factor(HDGF) was up-regulated during recovery of SIC and inhibition of HDGF reduced cardiac function, calcium cycling and contractility of myocytes. Expression of Inhibitor-1(I-1) was increased in the recovery phase, and exogenous HDGF induced I-1 expression, promoted calcium cycling and recovery of cardiac function. These results suggested the important role of HDGF in calcium handling during recovery of SIC. HDGF has not been reported to be functioning in SIC currently. Therefore, we hypothesized that: HDGF improves myocytes calcium handling performance and ameliorate cardiac function through I-1 up-regulation. This project will apply SIC mouse model induced by over-dose injection of isopreterenol to identify the role of HDGF in cardiac function recovery of SIC; explore the molecular mechanism in I-1-dependent regulation of calcium cycling and cardiac function recovery induced by HDGF. This project will novelly focus on function of HDGF in recovery phase of SIC to study the mechanism of SIC, and it may provide new strategy for SIC treatment and promotion of cardiac function.

应激性心肌病（SIC）引起暂时性心功能障碍，钙转运紊乱是SIC的发病机制之一，但其恢复机制目前仍不清楚。前期发现，肝细胞瘤衍生生长因子（HDGF）在SIC恢复期表达上调。抑制HDGF的表达降低钙转运及心肌功能的恢复。抑制因子-1（I-1）在恢复期表达增加，且HDGF可促进I-1的表达，提高心肌功能。结果提示HDGF在SIC恢复期钙转运中起重要作用。目前未见关于HDGF在SIC中的研究报道。据此，我们提出假说：HDGF可通过调控I-1的表达，改善心肌细胞钙转运，促进SIC心肌功能的恢复。本研究运用过量异丙肾上腺素诱导SIC模型，拟从分子、细胞以及动物水平等多层次明确HDGF在SIC心肌功能恢复中发挥的作用；探究HDGF通过调控I-1的表达影响心肌钙转运及心肌功能恢复的分子机制。本项目将从心功能恢复期HDGF的改变这一新视角探讨SIC心肌功能的恢复机制，为治疗SIC和促进心功能恢复提供新思路。

应激性心肌病可引起暂时可逆的心肌功能障碍，其中钙转运与心肌细胞收缩功能异常是重要的病理机制。探索应激性心肌病发病及其可逆恢复的机制是治疗该病，降低该病死亡率的关键。本研究针对肝细胞瘤衍生生长因子（HDGF）在应激性心肌病发病至转归过程中不同阶段的表达变化规律，深入研究发现HDGF可通过I-1表达的变化，对应激性心肌病的心肌恢复其作用。同时，发现外源性HDGF可有效促进应激性心肌病的心功能恢复，改善其血流动力学。本研究为应激性心肌病的理论机制提供新的思路，并为应激性心肌病的新药研发，提供理论基础。本研究还建立了重症数据库，并通过数据库对重症患者的监测和回顾分析，探索应激性心肌病的临床特征、药物疗效及预后特点。本研究针对应激性心肌病节段性改变的特点，针对心肌组织的不同结构部位蛋白表达的特异性，发现BMPR2对右心肌收缩的特异作用，为应激性心肌病的节段性功能异常提供新的理论依据。