REDD1通过蛋白质合成/自噬降解调控心力衰竭的机制研究

Heart failure is the end-stage outcome of many cardiovascular diseases. Cardiac hypertrophy is the core mechanism of the development of heart failure. The imbalance of protein synthesis and degradation contributes to the pathogenesis ofcardiac hypertrophy and heart failure. REDD1 is a newly-found stress-induced protein, which plays important roles in the regulation of protein synthesis and autophagic degradation. There’s no study illustrating the relation between REDD1 and heart failure. Our previous studies discovered that knockdown of REDD1 deteriorated cardiomyocyte hypertrophy; the pro-hypertrophic effect of REDD1 knockdown was partly resulted from the impairment of autophagy. Therefore,our previous results indicated that REDD1 might be involved in the regulation of the development of heart failure. In the present study, with REDD1 conditional transgenic and knockout mice,we aim to study the effects of the gain and loss of REDD1 function on pressure overload induced cardiac hypertrophy and heart failure. Moreover, we evaluate the regulation of protein synthesis and autophagy by REDD1 and further explore the underlying mechanism involved, so as to elucidate whether REDD1inhibit cardiac hypertrophy and heart failure by the amelioration of the imbalanceof protein synthesis and autophagic degradation. Consequently, the present studycould provide the proofs of new treating target genes for the therapy of heart failure.

心力衰竭是心脏疾病发展到终末期的表现，心肌肥厚是导致心力衰竭的核心环节，蛋白质合成/降解失衡是促进心肌肥厚和心力衰竭的重要机制。REDD1是近年发现的应激反应蛋白，对蛋白质合成/自噬降解具有重要调控作用，然而尚无REDD1与心力衰竭关系的报道。我们前期结果表明，沉默REDD1可促进心肌细胞肥厚，并且REDD1抑制心肌肥厚与促进自噬相关，因此，细胞研究结果提示REDD1可能对心力衰竭具有重要调控作用。本研究拟利用REDD1条件性转基因与基因敲除小鼠，通过压力过负荷诱导的心肌肥厚模型，从功能获得与缺失两方面研究REDD1对心肌肥厚与心力衰竭的调控作用，并深入探讨REDD1对蛋白质合成与自噬降解的调控作用及其分子机制，旨在阐明REDD1降低蛋白质合成与促进自噬、提高蛋白质降解是否为其抑制心肌肥厚、改善心力衰竭的核心机制，从而为心力衰竭的治疗提供新靶点和理论依据。

心力衰竭是多种心脏疾病进展的终末阶段。发育及DNA损伤反应调节基因1（Regulated in development and DNA damage responses 1，REDD1）是一种多功能蛋白，研究表明在缺氧、饥饿等应激情况下，REDD1可被诱导表达进而发挥多种保护性作用，目前尚无REDD1与心力衰竭关系的研究。本研究成功构建心肌条件性REDD1转基因小鼠，通过胸主动脉缩窄术构建压力过负荷诱导的心力衰竭动物模型，4周后对小鼠进行超声心动图分析及检测心功能相关指标，发现心肌条件性过表达REDD1显著促进小鼠心力衰竭，表现为心肌收缩能力下降以及明显加重的肺水肿。为深入研究REDD1促进心力衰竭的机制，本研究对下游可能涉及的信号通路蛋白进行了探索，结果显示REDD1可以调控细胞凋亡，过表达REDD1可显著促进细胞凋亡的发生，提示REDD1可能通过调控细胞凋亡影响心力衰竭的发生和发展。因此，本研究的发现可能为心力衰竭的预防和治疗提供理论依据和治疗靶点。

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