心脏特异性过表达Maf1调控心力衰竭的机制研究

One of the most important factors in the development of heart failure is ventricular remodeling which resulted from cardiac hypertrophy and fibrosis. The imbalance between protein synthesis and degradation in cardiomyocytes is a pivotal mechanism for remodeling progression.In our previous study,with adenoviral transfection and silencing of Maf1, we proved Maf1 could significantly inhibit cardiac hypertrophy, the effect related to that Maf1 can block RNA polymerase III, repress transcription so as to inhibit protein synthesis finally. Moreover, in cardiac specific Maf1 transgenic mice, we found overexpressed Maf1 could improve heart failure,decrease hypertrophy and fibrosis induced by pressure overload, with enhanced autophagy level.Therefore,in the present study,we aim to further the research of molecular mechanisms in heart failure and?explore the role of Maf1 in remodeling in vivo and in vitro, in order to elucidate whether blocking protein synthesis by transcription inhibition and inducing protein degradation by autophagy are key mechanisms of Maf1 repressing remodeling as well as improving heart failure. Consequently,the present study could provide proofs for new treating targets of heart failure.

心肌肥厚与纤维化导致的心室重构是心力衰竭发生发展的重要因素，蛋白质合成和降解失衡为引起心室重构的主要机制之一。在前期研究中，我们在心肌细胞中利用重组腺病毒转染过表达和基因沉默Maf1均证实Maf1可明显抑制心肌肥厚，此效应与Maf1抑制RNA聚合酶III、抑制转录、减少蛋白质合成相关。并且，在压力过负荷诱导的心力衰竭中，利用心脏特异性过表达Maf1转基因小鼠，我们发现过表达Maf1明显改善心力衰竭，伴随着降低的心肌肥厚与心肌纤维化，同时心脏自噬水平升高。因此，为深入研究Maf1对心力衰竭的调控机制，本研究拟通过心脏特异性过表达Maf1转基因小鼠和腺病毒转染过表达Maf1，从动物和细胞水平探讨Maf1对心室重构的调控作用，并深入分析其机制，旨在阐明Maf1调控转录、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室重构、拮抗心力衰竭的核心机制，为心力衰竭的临床治疗提供新靶点和理论依据。

心肌肥厚是各种心血管疾病死亡的独立危险因素，其持续存在导致心力衰竭的最终发生。本研究通过构建Maf1基因敲除小鼠、心脏条件性Maf1转基因小鼠以及腺病毒注射过表达Maf1，并且在心肌细胞通过腺病毒转染过表达Maf1的小干扰RNA沉默技术，从动物和细胞水平研究了Maf1对心肌肥厚的调控作用，旨在阐明Maf1调控转录、自噬是否为其抑制心室重构、拮抗心力衰竭的核心机制，为心肌肥厚及心力衰竭的临床治疗提供新靶点和理论依据。在本研究进行当中，本课题组利用压力过负荷和苯肾上腺素（PE）所诱导的体内外心肌肥厚模型，首次证明了1）敲除或者沉默Maf1可促进PE及压力过负荷诱导的心肌肥厚的发生发展，促进心力衰竭的发生；2）过表达Maf1可抑制PE及压力过负荷诱导的心肌肥厚的发生发展以及心力衰竭的发生；3）Maf1对于心肌肥厚的抑制作用与其对于自噬及转录的调控相关；基本阐明了Maf1调控转录及蛋白质合成对心肌肥厚发生发展的影响及其分子机制，为心肌肥厚及心力衰竭的早期干预与治疗提供理论依据和治疗靶点。

内容获取失败，请点击重试