Circ-LTBP2-miR-34a-ALDH2调控通路在压力超负荷心衰能量代谢重塑中的作用及机制研究

Pressure overload is a leading cause of heart failure, which occurs in many clinical settings such as hypertension, valvular heart disease and pulmonary hypertension. Heart failure induced by pressure overload has worse prognosis and fewer treatments compared to other overload stress. Myocardial energy metabolism remodeling plays the key role in its pathogenesis, but the underlying mechanism remains unclear. Recent research showed circular RNA-HRCR protects the heart from pathological hypertrophy and heart failure by targeting miRNA. We previously identified circ-LTBP2 was significantly changed in the heart tissues of pressure overload induced heart failure patients compared to matched normal tissues and bioinformatic analysis revealed it can be bounded by miR-34a. Besides, we identified ALDH2 as a miR-34a downstream target to regulate myocardial energy metabolism. Based on these results, we proposed the hypothesis that circ-LTBP2 acts as an endogenous miR-34a sponge to regulate myocardial energy metabolism through ALDH2. In this study, we plan to perform gain or loss of function of circ-LTBP2/miR-34a/ALDH2 experiments in pressure overload cell and animal models, in order to verify the role and mechanism of circ-LTBP2-miR-34a-ALDH2 regulation axis. This study will extend our understading of complex mechanisms of myocardial energy metabolism remodeling and contribute to the potential clinical targeted therapy.

压力超负荷是心力衰竭常见病因，所致心衰死亡率高，治疗手段有限。心肌能量代谢重塑是压力超负荷心衰病理生理机制关键环节，但调控机制尚待明确。新近研究报道环状RNA-HRCR可以靶向调控miRNA抑制压力超负荷心衰进展。我们前期研究发现circ-LTBP2在压力超负荷心衰患者组织中改变显著，且生物信息预测circ-LTBP2可以与miR-34a结合，而既往研究证实miR-34a可靶向调控能量代谢关键蛋白ALDH2。据此我们提出假说:circ-LTBP2可以通过分子海绵作用抑制miR-34a表达，进而调控ALDH2参与压力超负荷心衰能量代谢重塑过程。为求验证，我们拟利用细胞、小鼠压力超负荷模型，沉默或上调circ-LTBP2/miR-34a/ALDH2轴检测其对能量代谢体系影响。本研究将从环状RNA这个新视角揭示压力超负荷心衰能量代谢重塑调控机制，为心衰的防治提供新思路。

心肌能量代谢重塑是压力超负荷心衰病理生理机制关键环节，但调控机制尚待明确。课题组前期研究发现circ-LTBP2在压力超负荷心衰患者组织中改变显著，且生物信息预测circ-LTBP2可以与miR-34a结合，而既往课题组已经证实miR -34a可靶向调控能量代谢关键蛋白ALDH2。本课题证实circ-LTBP2-miR-34a轴作为ALDH2上游调控通路在压力超负荷心衰能量代谢调控中起重要作用。上调circ-LTBP2可通过分子海绵作用进一步下调miR-34a水平，改善心衰过程中葡萄糖、脂肪酸摄取失衡及整体能量代谢状态、能量代谢储备紊乱。同时进一步发现该调控轴在免疫检查点抑制剂心肌炎症及心功能不全中亦起关键调控作用。为相关心衰调控提供了潜在干预治疗靶点。