心肌细胞衰老与心脏疾病的发生密切相关，缺氧是诱发心肌衰老的常见因素。虽然已部分揭示了缺氧导致心肌衰老与心肌结构、代谢和电重构之间的关系，但果糖代谢在心肌衰老中的作用仍不清楚。我们前期发现①miR-155-/-小鼠抗缺氧能力显著增强；②缺氧激活miR-155-/-小鼠心肌果糖代谢；③缺氧促进HIF1α pre-mRNA选择性剪接形成circHIF1α。由此我们提出低氧诱导的miR-155-RNA结合蛋白-circHIF1α-KHK-C(果糖代谢关键酶)轴促进心肌衰老的假设。本项目主要研究①miR-155及受其调控的RNA结合蛋白在调节HIF1α pre-mRNA选择性剪接形成circHIF1α和HIF1α mRNA中的作用；②circHIF1α调节KHK-C表达和活性的分子机制；③miR-155在缺氧触发心肌以果糖代谢为特征的代谢重构中的作用及分子机制，为防治缺氧引起的心肌衰老提供新的思路

Myocardial cell senescence is closely related to the occurrence of cardiac diseases. Hypoxia is a common factor inducing myocardial senescence. Although the relationship between myocardial aging caused by hypoxia and myocardial structure remodeling, metabolism remodeling and electrical remodeling has been partly revealed, the role of fructose metabolism in myocardial aging remains unclear. Previously, we found that: ① miR-155-/- mice against hypoxia; ②hypoxia activated the myocardial fructose metabolism in miR-155-/- mice; ③hypoxia promoted the selective splicing of HIF1α pre-mRNA to form circHIF1α. Therefore, we hypothesized that hypoxia-mi-R155-RNA binding protein-circHIF1α-KHK-C (key enzyme of fructose metabolism) axis promotes myocardial aging. This project mainly studied ①the role of miR-155 and its regulated RNA binding proteins in regulating HIF1α pre-mRNA selective splicing to form circHIF1α and HIF1α mRNA; ②the molecular mechanism of circHIF1α regulating the expression and activity of KHK-C; ③ the role and mechanism of miR-155 in triggering myocardial metabolic remodeling characterized by fructose metabolism under hypoxia. This project provide a new idea for preventing and treating myocardial aging caused by hypoxia.