circRNA-VDAC参与心肌缺血再灌注损伤的调控作用及其机制

Myocardial ischemia / reperfusion injury (MIRI) is a common cardiac injury after cardiopulmonary bypass (CPB). The occurrence of myocardial ischemia reperfusion injury is a complex process involving many factors, which requires more comprehensive and in-depth scientific research. Studies have shown that circRNA is involved in the process of different cardiac diseases by controlling miRNA, but whether it has played a role in myocardial ischemia and reperfusion has not been reported. We found that circRNA-VDAC expression was significantly up-regulated during myocardial ischemia and reperfusion in previous studies in vitro and in vivo model, cell damage function preliminary study also suggested that inhibition of circRNA-VDAC expression in the cell can improve ischemia reperfusion induced. These results suggest that circRNA-VDAC is involved in the process of ischemia reperfusion injury, but its function and mechanism are not clear. Through this study, we will clarify the mechanism of circRNA-VDAC in myocardial ischemia reperfusion injury through studying the function of circRNA-miRNA，circRNA-protein and circRNA-DNA , and the possibility of circRNA-VDAC as a mark of clinical treatment and detection.

心肌缺血再灌注损伤(MIRI)是心脏体外循环术后常见的损害，其发生是一个涉及多因素的复杂过程，需要更全面、更深入的科学研究。CircRNA通过对miRNA的调控，在心血管疾病的病理生理中发挥着重大作用，但其在心肌缺血再灌注中的作用尚未报道。我们在前期研究中通过体外和体内模型发现circRNA-VDAC在心肌缺血再灌注过程中表达显著上调，初步的功能研究也提示在细胞中抑制circRNA-VDAC的表达能改善缺血再灌注导致的细胞损伤。上述结果提示circRNA-VDAC参与缺血再灌注损伤过程，但是其功能和具体机制尚不明确。在此基础上我们将从circRNA-miRNA、circRNA-蛋白、circRNA-DNA等不同角度进一步深入研究circRNA-VDAC参与心肌缺血再灌注损伤的机制，初步探索circRNA-VDAC作为调控靶点的前景以及临床检测标志物的可能性。

心肌缺血再灌注损伤(MIRI)是心脏体外循环术后常见的损害，其发生是一个涉及多因素的复杂过程，需要更全面、更深入的科学研究。CircRNA通过对miRNA的调控，在心血管疾病的病理生理中发挥着重大作用，但其在心肌缺血再灌注中的作用尚未报道。基于前期基础，本项目从circRNA-蛋白的角度深入研究circRNA-VDAC参与心肌缺血再灌注损伤的机制，探索了circRNA-VDAC作为调控靶点的前景以及临床检测标志物的可能性。.项目执行期间，通过细胞和动物的再灌注损伤模型筛选到circRNA-VDAC参与心肌缺血再灌注损伤过程。CircRNA-VDAC的表达增加与单纯缺氧无明显关系，而仅在再灌注损伤后显著升高。通过siRNA介导的circRNA-VDAC的表达沉默，发现抑制circRNA-VDAC显著加重再灌注诱导的心肌细胞损伤和线粒体氧化应激程度。动物水平的circRNA-VDAC表达抑制，发现心脏损伤显著加重，血清CK、cTnI水平增加，心脏梗死面积增加，心肌细胞凋亡数量增加，提示心脏缺血再灌注损伤后可能通过上调circRNA-VDAC表达，进而发挥心脏保护作用。通过生物信息学软件进行预测，发现Sirt1和PGC1α可能是circRNA-VDAC调节线粒体功能的重要靶分子。CircRNA-VDAC表达与Sirt1和PGC1α表达具有相关性，抑制circRNA-VDAC引起Sirt1和PGC1α表达的明显下降。抑制circRNA-VDAC表达后，Sirt1和PGC1α表达下降，从而引起心脏线粒体过氧化物生成量显著增加、膜电位降低、ATP 生成量减少，提示circRNA-VDAC对线粒体的功能存在显著影响。临床样本的检测发现， circRNA-VDAC在PCI术后再灌注损伤的患者循环血中的水平显著高于无再灌注损伤的患者，可作为心肌缺血再灌注损伤的标志物。.项目组共发表SCI收录论文2篇。授权国家发明专利1项。协助培养博士研究生1名。