核酸小分子和支链氨基酸代谢物在病理性心肌重构中的作用

Cardiac dysfunction is the common outcome of pathological cardiac remodeling induced by multiple cardiac diseases. Branched-amino acids(BCAAs) metabolites play important role in regulation of pathological cardiac remodeling and dysfunction.Our previously study shown that the key metabolic enzymes of BCAAs and cardiac remodeling were affected by several miRNAs, the expression of these miRNA was altered in the serum and heart tissues of patients and mouse with pathological cardiac remodeling. Besides miRNA, circRNA andt RNA have also regulated the transcription of target genes. However, the role of interaction between nucleic acid small molecule and BCAAs metabolites in pathological cardiac remodeling was still unknown.The aims of our project are: 1) to focus on the interaction among BCAAs-derived small bioactive molecules,miRNA, circRNA and tRNA;2) to choose the key target by transcriptomic and metabolomics analysis of the serum and heart tissues with pathological cardiac remodeling; 3) to confirm the detailed mechanism of miRNA, circRNA and tRNA in cardiac remodeling and dysfunction by interaction with the key metabolic enzymes and metabolites of ARA. This studies will further facilitate to discover novel endogenous small bioactive molecules as the therapeutic targets for heart failure.

心力衰竭是多种心血管疾病导致心肌重构的共同结果，支链氨基酸代谢物对心肌重构与心力衰竭的发生发展具有调控作用。研究发现病理性心肌重构患者和小鼠的血清和心脏组织中多个miRNA表达发生改变，并影响支链氨基酸代谢酶的表达和病理性心肌重构过程。除miRNA外，其他核酸小分子circRNA,tRNA也具有转录调控作用。但这些核酸小分子与支链支链氨基酸代谢活性小分子之间的相互调节在病理性心肌重构过程中的作用等科学问题尚不清楚。本课题将以支链氨基酸代谢活性小分子与核酸小分子间的调控为核心，通过对心肌梗死后发生心脏重构的心脏组织和血清中各种核酸小分子的组学分析和支链氨基酸代谢物的质谱数据选择研究靶点，明确核酸小分子通过与支链氨基酸代谢通路中关键酶或产物的相互作用影响心肌重构和心力衰竭发生的分子机制。本研究将为心肌梗死后心力衰竭的治疗提供新靶点。

心力衰竭是多种心血管疾病导致心肌重构的共同结果，支链氨基酸代谢物对心肌重构与心力衰竭的发生发展具有调控作用。支链氨基酸（BCAAs）包括亮氨酸、缬氨酸和异亮氨酸三种氨基酸。除了是蛋白质合成的重要成分，支链氨基酸代谢的改变还是心肌重构及心力衰竭发生发展中关键的事件，其中调控酶的改变是影响支链氨基酸代谢的重要分子事件，表观调控如miRNA对相关蛋白的表达与作用起到重要的影响。本研究关注在调控代谢的关键酶支链酮酸脱氢酶(BCKD, branched chain keto acid dehydrogenase)等，更进一步在表观修饰水平去寻找可以调控关键酶的miRNA。首先我们整合了来自Gene card网站的可调控支链氨基酸代谢的关键酶branched chain keto acid dehydrogenase (BCKD)的miRNA 43个，以及来自文献报道的与心力衰竭相关的11个miRNA，最终确定了2个与心力衰竭病理过程相关的miR-485-5p以及miR-92b-3p。进一步我们在小鼠缺血再灌注损伤模型和AII灌泵模拟心衰模型中分别进行体内干预，通过评估心脏功能及纤维化改变，我们最终揭示了mir-92b-3p治疗组可显著减轻心衰过程中心肌细胞的肥大改变并显著减轻了心脏的纤维化程度；本研究发现在心脏损伤过程中mir92b-3p可通过影响支链氨基酸代谢关键酶BCKD进而参与到心衰的发生发展过程中，为心脏重塑的治疗提供了潜在的思路。