靶向抑制腺苷激酶经去DNA甲基化修饰胰岛素样生长因子-1改善缺血再灌注心肌能量代谢

Adenosine kinase (ADK) is a key enzyme for cellular adenosine metabolism, and catalyzes adenosin into AMP, which regulates downstream metabolism and DNA methyaltion modification. Latest studies indicated that myocardial energy metabolism could be regulated via direct crosstalk to epigenetic modification. Though ADK inhibition attenuated myocardial ischemia-reperfusion injury, the non-specificity inhibition of ADK caused adverse side events. In addition, little was known about the effect of ADK on myocardial energy metabolism. Our preliminary study indicated that targeted inhibition of myocardial ADK regulated DNA methylation of metabolism genes (such as IGF-1) via methyl metabolism, and ameliorated ischemia-reperfusion injury. Accordingly, we hypothesized that targeted inhibition of myocardial ADK could improve myocardial energy metabolism via demethylation modification of IFG-1 so as to attenuate ischemia-reperfusion injury. Our study will be further carried on with myocardial specific ADK knockout mice to establish the ischemia-reperfusion model and multiple experiments, including the culture of adult mice myodium in vitro, detection of DNA methylation and searhorse assay of energy metabolism. Our study is aimed to explore the effect of ADK on myocrdial energy metabolism via IGF-1 pathways, and provide novel evidence and targets for prophylaxis and treatment of ischemia-reperfusion.

腺苷激酶（adenosine kinase，ADK）是调控细胞腺苷代谢的关键酶之一，催化细胞内腺苷转化为一磷酸腺苷，影响细胞代谢及DNA甲基化。最新研究提示，经表观遗传的直接交互作用可调控心肌能量代谢。尽管ADK抑制剂可以缓解心肌缺血再灌注损伤，但非特异性干预ADK往往存在诸多不良副作用。另外，少有研究探索ADK对于缺血再灌注心肌能量代谢的影响。我们前期研究发现靶向敲除心肌ADK能够经甲基代谢途径调控IGF-1等代谢基因的DNA甲基化修饰，缓解缺血再灌注损伤。因此，我们提出假说：靶向抑制ADK通过IGF-1去甲基化修饰改善心肌代谢，最终缓解心肌缺血再灌注损伤。本研究将利用已获得的ADK心肌特异敲除小鼠，构建缺血再灌注模型，采用成年小鼠心肌离体培养、甲基化测定及seahorse能量代谢检测等技术。探索ADK靶向抑制经IGF-1通路对心肌能量代谢的调控作用，为缺血再灌注防治提供新的证据及靶点。

项目组致力于心肌保护的能量代谢与表观遗传交互作用及转化研究，以心肌腺苷代谢为切入点，证明了靶向调控甲基代谢相关表观遗传修饰经线粒体代谢途径改善缺血再灌注损伤；揭示了ADK对心肌能量代谢和表观遗传的交互作用及相关机制，并完成了临床转化。具体成果包括，揭示了ADK经DNA甲基化表观修饰IGF-1进而改善缺血再灌注心肌损伤，为心衰代谢干预提供了新靶点；发现了线粒体关键代谢酶经自噬途径增加糖尿病患病风险，对糖尿病高危人群筛选及降糖治疗靶点选择提供了新的理论依据；证实了传统药物硫辛酸改善心衰患者线粒体代谢的治疗潜力，并完成专利转化。共有以第一作者身份完成论文1篇，病例报道1篇，参与发表论文1篇。获得国家发明专利授权2项，转化1项，相关成果获得上海医学科技奖一等奖，上海市科技进步奖一等奖。