REDD2通过改善能量代谢重构抑制心力衰竭的机制研究

Heart failure is the end-stage outcome of various cardiovascular diseases. Cardiac hypertrophy is one of the important mechanisms involved in the pathogenesis of heart failure. Energy metabolic remodeling is the core mechanism that contributes to the transition from cardiac hypertrophy to heart failure. REDD2 is a newly-found protein which protects against stresses. However, whether REDD2 regulates energy metabolism and heart failure remains unknown. In our previous studies, we discovered that REDD2 knockdown by siRNA transfection significantly inhibited AMPK, the regulator of energy metabolism, accompanied with the impairment of fatty acid transportation. Moreover, REDD2 knockdown deteriorated cardiomyocyte hypertrophy induced by phenylephrine. These data revealed that REDD2 might inhibit cardiac hypertrophy and heart failure by modulation of energy metabolism. In this study, we aim to explore the regulatory effect of phenylephrine induced cardiomyocyte hypertrophy and pressure overload induced heart faliure by REDD2 with siRNA and adenovirus transfection in vitro and cardiac-specific conditional REDD2 knockout mice in vivo. We further plan to illustrate whether the effect of REDD2 on the improvement of energy metabolic remodeling is the core mechanism involved in the regulation of cardiac hypertrophy and heart faliure. Therefore, this study could provide a new target and the related theoretical basis for the prevention and therapy of heart failure.

心力衰竭是多种心血管疾病进展至终末期的临床表现，心肌肥厚是心力衰竭发生、发展的核心机制。心肌能量代谢重构是心肌肥厚向心力衰竭进展的重要分子机制之一。REDD2是近年新发现的功能蛋白，目前尚无REDD2调控能量代谢及其对心力衰竭调控作用的报道。我们的预实验发现，小干扰RNA转染沉默REDD2蛋白可抑制能量代谢调控因子AMPK的激活及脂肪酸转运，并且促进苯肾上腺素诱导心肌细胞肥厚；基于此，我们推断REDD2可能通过改善能量代谢重构，抑制心肌肥厚与心力衰竭的进展。本研究拟在苯肾上腺素诱导心肌肥厚及压力过负荷诱导心力衰竭模型中，利用小干扰RNA及腺病毒转染，并构建心脏条件性REDD2基因敲除小鼠，深入探讨REDD2对心肌肥厚与心力衰竭的调控作用及其分子机制，旨在阐明改善能量代谢重构是否为REDD2抑制心肌肥厚、改善心力衰竭的核心机制，为临床心力衰竭的预防及治疗提供新靶点和可靠的科学理论依据。

心力衰竭是多种心血管疾病终末期的共同转归，心肌肥厚是心力衰竭进展的核心过程，积极抑制心肌肥厚可有效延缓甚至抑制心力衰竭的发生和发展。因此，探索心肌肥厚的负性调控靶点可进一步明确心力衰竭的机制。本研究明确了REDD2蛋白可对心肌肥厚具有重要调控作用。在机制研究方面，基于心力衰竭过程中显著的能量代谢重构，本课题致力于以代谢重构为研究核心。本研究阐明了REDD2对脂肪酸代谢和葡萄糖代谢的具体调控作用，发现了REDD2可促进心肌肥厚过程中的高效产能的脂肪酸代谢并抑制低效产能的葡萄糖酵解，通过提高产能效率改善心肌肥厚过程中的能量缺乏以发挥保护作用。此外，基于心肌梗死是心力衰竭的主要病因，本研究亦初步探索了REDD2在心肌梗死后心室重构中有潜在的调控作用。为进一步拓展以能量代谢重构为心衰治疗目标的临床转化作用，课题组证明了新型药物高车前素可抑制心肌肥厚和心力衰竭，并显著促进脂肪酸代谢产能和葡萄糖代谢产能。因此，本研究在心肌肥厚和心力衰竭领域，以改善能量代谢重构为出发点进行了靶点探索和药物研究，为心力衰竭新的治疗药物和模式提供新的思路。