染色质重塑因子BAF60c调控心肌氧化代谢相关基因表达的分子机制

"Bioenergetic starvation" is an important feature in systemic metabolic impairment which eventually leads to body tissue loss and cachexia. In the early stage of heart failure, cardiomyocytes have appeared energy metabolism disorders, including mitochondrial oxidative metabolism decreased, glycolysis increased, energy metabolism substrate converted to glucose, metabolic type to "fetal phenotype". BAF60c and PGC-1α are two factors that play a central role in myocardial development and energy metabolism, which is of great significance in the conversion between mitochondrial oxidative metabolism and glycolysis. Previous studies have shown that the expression of BAF60c in fetal heart failure is decreased, while the expression of PGC-1α is increased and mitochondria oxidative metabolism is enhanced. The results are opposite to adult heart failure. In vitro experiments showed that siRNA inhibited BAF60c caused up-regulation of PGC-1α and enhanced mitochondrial oxidative metabolism. Therefore, this project intends to investigate the differential metabolic regulation of energy metabolism in fetal heart/adult heart failure, and clarify the binding status, recruitment characteristics of BAF60c and PGC-1α, as well as the regulation of myocardial oxidative metabolism, and explore potential targets to promote mitochondrial oxidative metabolism , Enhance the efficiency of myocardial energy utilization, so as to provide new ideas for heart failure and systemic metabolic impairment.

"生物能量饥饿"是系统性代谢失衡及衰竭的重要特征，最终导致机体组织消耗及恶病质。心力衰竭（心衰）一直是系统性代谢失衡及衰竭的研究重点之一。心衰早期心肌即已出现能量代谢障碍，线粒体氧化代谢下降、糖酵解增强，能量代谢底物由脂肪酸向葡萄糖转变，代谢模式转换为“胎儿表型”。BAF60c和PGC-1α是心肌发育和能量代谢调控的核心因子。本团队前期研究发现，胎儿期衰竭心肌BAF60c表达下降，而PGC-1α表达升高，线粒体氧化代谢增强，与成年期心衰代偿特征相反。体外实验提示，siRNA抑制BAF60c可上调PGC-1α表达，并增强线粒体氧化代谢。因此，本项目拟从胎儿期/成年期心衰能量代谢调控的差异化代偿特征着手，阐明BAF60c与PGC-1α的结合状态、募集特征及对心肌氧化代谢的调控作用，为促进线粒体氧化代谢、增强心肌能量利用效率筛选潜在干预靶点，为心衰与系统性代谢失衡及衰竭诊治提供全新思路。

心肌代谢重构是心力衰竭(心衰)的重要病理生理特征，遗传因素和环境因素共同作用是导致心肌代谢重构的致病机理，然而细胞如何整合内外因素以调控心肌代谢转换的机制仍未明确。本研究利用异丙肾上腺素(ISO)羊膜腔内注射建立胎儿大鼠心衰模型，发现衰竭心脏与胚胎心脏基因表达具有高度相似性，成年期心肌代谢重构过程往往伴随着胎儿基因程序再激活。BAF60蛋白家族是染色质重塑复合物SWI/SNF的结构亚基，对于心肌代谢重编程和环境适应、细胞分化及胚胎发育发挥着重要作用。BAF60蛋白能够将SWI/SNF复合物与特定转录因子锚定，通过动态重塑染色质状态而调控细胞功能转换。本课题以心肌氧化代谢/糖酵解代谢转换为目标研究BAF60蛋白家族与能量代谢关键调控因子的分子机制。本研究发现，胎儿期心肌氧化代谢水平低，增殖能力强，以糖酵解为主，在胎儿心衰时，葡萄糖氧化代谢偶联作用增强，脂肪酸氧化代谢升高，线粒体快速趋于成熟，细胞增殖能力下降，更多的能量代谢底物进入氧化代谢途径，与成年期心衰呈现差异化代偿特征。通过视黄酸(RA)诱导H9C2细胞分化进一步发现，BAF60a能够调控PGC-1α表达且正相关，而BAF60c和PGC-1α表达负相关。BAF60a/BAF60c在生命各个阶段的时空演变规律是诱导SWI/SNF复合物调控心肌代谢转换从而适应环境改变的重要特征，PGC-1α是BAF60a/BAF60c调控心肌细胞代谢模式转换的关键靶点。通过上述研究，不仅从代谢重构的角度认识了心衰的发生机制，揭示了生命不同时期表观遗传学整合内外因素的动态调控角色，继而筛选出潜在干预靶点，为胎儿/成人心脏疾病的靶向治疗提供理论依据。项目资助发表论文4篇，其中SCI论文3篇，成果获得2019四川省医学科技进步奖一等奖。培养研究生3名，其中1名已取得博士学位。项目投入经费21万元，已支出13.26万元，各项支出与预算相符，剩余经费计划用于本项目研究后续支出。