Ghrelin对糖尿病大鼠缺血诱导的心肌血管新生障碍的影响及相关机制研究

It is thought that diabetic patients have impaired ischemic-induced myocardial neovascularization. Compared with patients without diabetes, those with the disease have low capillary density, reduced coronary artery collateral vessel formation during chronic myocardial ischemia. As the disease progresses, it will eventually lead to heart failure, which ultimately determines its poor prognosis. Ghrelin, a novel brain-gut peptide, is found to stimulate myocardial angiogenesis in vitro of SD rats in our previous studies and protect endothelial cells from high glucose-induced injury. However, there are no previous reports studying the effects and related mechanisms of ghrelin on ischemic myocardium revascularization in diabetic rats. Therefore, in our study, we explored the effects of ghrelin on impaired ischemic-induced myocardial neovascularization and whether the angiogenic effect induced by ghrelin is achieved by activation AMPK, GSK-3β and NF-kB signal pathways through up-regulation of VEGF, Flt-1 and Flk-1 mRNA and protein expression in diabetic rats. In this study, we investigated the effects and related mechanisms of ghrelin on ischemic myocardium revascularization of diabetic rats in the organ, cellular and molecular level for the first time. It might provide new ideas to stimulate neovascularization during myocardial ischemia in diabetic rats.

糖尿病普遍存在缺血诱导的心肌血管新生障碍，表现为微血管新生能力减弱，心肌微血管密度降低，侧枝循环形成减少，随着疾病进展导致心力衰竭的发生，这最终决定糖尿病的不良预后。Ghrelin一种新近发现的脑肠肽，我们前期研究证实能促进正常大鼠心肌微血管内皮细胞的体外血管生成和显著抑制高糖对血管内皮细胞的损害。然而，ghrelin是否可促进糖尿病大鼠缺血心肌血管新生及其相关机制，目前无研究报道。本研究以STZ诱导的糖尿病大鼠心肌梗死模型及原代培养的心肌微血管内皮细胞为对象，推测ghrelin可通过激活AMPK、GSK-3β和NF-kB信号途径来促进糖尿病大鼠缺血心肌血管新生，且上述效应可能与其参与调控VEGF、Flt-1和Flk-1的基因和蛋白表达有关。本课题首次在器官、细胞及分子水平上探讨ghrelin对糖尿病大鼠缺血心肌再血管化的效应及机制，为在缺血缺氧状态下刺激糖尿病大鼠心肌血管新生提供新思路。

糖尿病普遍存在缺血诱导的心肌血管新生障碍，表现为微血管新生能力减弱，心肌微血管密度降低，侧枝循环形成减少，随着疾病进展导致心力衰竭的发生，这最终决定糖尿病的不良预后。Ghrelin一种新近发现的脑肠肽，研究发现ghrelin可作为内源性血管新生的调节因子(促进或抑制血管新生)，且可显著抑制高糖对血管内皮细胞的损害。然而，ghrelin对糖尿病大鼠缺血心肌血管新生的影响及其相关机制，目前无研究报道。因此，本研究以糖尿病心梗大鼠为研究对象，探讨ghrelin对糖尿病大鼠缺血诱导的血管新生的影响及相关机制。我们的研究发现：①ghrelin可促进糖尿病心梗大鼠缺血心肌微血管新生。②ghrelin可显著提高糖尿病心梗大鼠左室射血分数(LVEF)和左室短轴缩短率(FS)。③ghrelin可通过上调糖尿病心梗大鼠缺氧诱导因子(HIF1α)、血管内皮细胞生长因子(VEGF)及其受体(Flk-1、Flt-1)的表达来促进缺血心肌的血管新生。④ghrelin是通过激活AMPK/eNOS的磷酸化促进糖尿病缺血心肌的血管新生。⑤GHSR-1a阻断剂[D-Lys3]-GHRP-6可显著抑制ghrelin的上述效应，提示ghrelin是通过与GHSR-1a的特异性结合来发挥其生理效应的。本研究证实ghrelin可通过GHSR-1a依赖AMPK/eNOS通路促进HIF1α、VEGF及其受体Flk-1、Flt-1的表达来促进糖尿病缺血心肌的血管新生。本研究在器官、细胞及分子水平上探讨ghrelin对糖尿病大鼠缺血心肌再血管化的效应及机制，为在缺血缺氧状态下刺激糖尿病大鼠心肌血管新生提供新思路。