运动预适应上调lncRNA Mhrt779通过激活Nrf2/HO-1抑制铁死亡改善糖尿病性心肌病的机制研究

糖尿病性心肌病（DCM）早期舒张功能不全（HFpEF）,但后者缺乏有效的治疗手段，而预防可能有效。我们前期研究证明了运动肥厚预适应（EHP）现象，即生理性心肌肥厚消退后仍可抵抗病理性心肌肥厚并改善心脏收缩和舒张功能。那么，EHP是否也能改善DCM-HFpEF？如果能，机制是什么？研究表明Brg1促进Nrf2/HO-1通路活化，而Nrf2/HO-1轴抑制铁死亡。我们前期研究表明EHP诱导的lncRNA Mhrt779可与Brg1结合。因此，我们假设EHP产生的Mhrt779通过与结合Brg1促进Nrf2/HO-1轴活化，抑制心肌细胞铁死亡，进而改善DCM。本项目将在前期研究基础上，通过Mhrt779过表达及干扰分析EHP对DCM和铁死亡的影响；采用RIP、CoIP等方法分析Mhrt779参与EHP改善DCM-HFpEF的作用机制；本项目的完成有望为DCM-HFpEF治疗提供新的策略和靶点。

Early diastolic insufficiency (DCM-HFpEF) caused by diabetic cardiomyopathy is a critical period for the clinical treatment of DCM. We have previously proved the phenomenon of preconditioning for exercise hypertrophy (EHP), that is, after physiological myocardial hypertrophy subsides, it can still resist pathological myocardial hypertrophy and improve cardiac systolic and diastolic function. So, can EHP also improve DCM-HFpEF? If so, what is the mechanism? Previous studies have shown that Brg1 promotes the activation of the Nrf2/HO-1 pathway, while the Nrf2/HO-1 axis inhibits ferroptosis. Our previous studies have shown that EHP-induced lncRNA Mhrt779 can bind to Brg1. Therefore, we hypothesized that Mhrt779 produced by EHP promotes the activation of the Nrf2/HO-1 axis by combining with Brg1, inhibits ferroptosis of cardiomyocytes, and thereby improves DCM. This project will analyze the effect of EHP on DCM-HFpEF and ferroptosis through Mhrt779 overexpression and interference analysis on the basis of previous research; use RIP, CoIP and other methods to analyze the mechanism of Mhrt779 participating in EHP to improve DCM-HFpEF; The completion is expected to provide new strategies and targets for the treatment of DCM-HFpEF.