生理性缺血训练介导循环外泌体通过LncRNA ECI2/GATA4调控远隔缺血心肌内皮细胞增殖的机制研究

Physiological ischemic training (PIT), which is capable to promote the formation of collateral circulation and improve cardiac reperfusion, is one of the promising interventions in cardiac rehabilitation. Our preliminary results showed that the concentration of exosome and proliferation level of endothelial cell were up-regulated in both plasma and ischemic myocardium after PIT. The in vitro tracing experiment demonstrated that circulating exosome was capable to get into the endothelial cell. The expression level of LncRNA ECI2 and GATA4 in the circulating exosome were up-regulated in the plasma in the patients with coronary heart disease (CHD). Luciferase Assay further presented the targeted binding between LncRNA ECI2 and GATA4. All the above results indicated that the expression of LncRNA ECI2 and GATA4 in the circulating exosome may play a part in the PIT-regulated endothelial cell proliferation in the remote ischemic myocardium. In this project, the effects of PIT, which may promote the formation of collateral circulation and improve cardiac reperfusion, will be investigated in the molecular, cellular, histionic and animal level. The role of LncRNA ECI2/GATA4 in regulating endothelial cell proliferation and angiogenesis in PIT will be explored. The clinical correlation between the expression level of LncRNA ECI2 and GATA4 in the circulating exosome and the effectiveness of cardiac rehabilitation will also be clarified.

生理性缺血训练（Physiological ischemic training, PIT）是冠心病康复中一种极具潜力的治疗方法，可以促进远隔缺血心肌侧支循环生成，改善血流灌注。我们前期研究发现，PIT干预后大鼠外周血和缺血心肌中外泌体粒浓度、内皮细胞增殖水平显著提高；体外示踪实验显示循环外泌体可以进入内皮细胞；PIT后冠心病患者外周血中循环外泌体LncRNA ECI2/GATA4表达水平显著增高；Luciferase验证了LncRNA ECI2与GATA4 mRNA的靶向结合，提示PIT可能通过介导循环外泌体运载LncRNA ECI2和GATA4至远隔缺血心肌调控内皮细胞增殖。本课题拟从分子、细胞及动物水平研究循环外泌体LncRNA ECI2/GATA4在PIT过程中调控内皮细胞增殖的调控机制，明确循环外泌体LncRNA ECI2/GATA4与冠心病康复疗效的相关性。

生理性缺血训练（Physiological ischemic training，PIT）是冠心病康复中一种极具潜力的治疗方法，可以促进远隔缺血心肌侧支循环生成，改善血流灌注。我们研究发现，PIT干预后大鼠外周血和缺血心肌中外泌体内LncRNA TUG1表达水平明显降低、内皮细胞增殖水平显著提高；体外示踪实验显示循环外泌体可以进入内皮细胞；PIT后冠心病患者外周血中循环外泌体LncRNA TUG1的表达水平显著下降；Luciferase验证了LncRNA TUG1与HIF-1α mRNA的靶向结合。提示PIT通过介导循环外泌体运载LncRNA TUG1至远隔缺血心肌激活HIF-1α通路调控内皮细胞增殖。