Ghrelin 对内皮祖细胞参与间歇性低氧大鼠心梗后血管新生的影响及作用机制

The overlap of obstructive sleep apnea and coronary artery disease is common, affecting the events of acute myocardial infarction (AMI). Intermittent hypoxia (IH) related endothelial injury is the primary player in this process. It is well known that in patients with reduced LVEF in AMI the mobilization of endothelial progenitor cells (EPCs) is less efficient for the participation in vascular and cardiac repair, which might contribute to the promotion of heart failure. However, whether this phenomenon exists in the setting of AMI with concomitant IH is still unknown. Some previous studies found that serum ghrelin levels were significantly lower on admission in AMI patients. Furthermore, exogenous ghrelin significantly improved LVEF induced by AMI. Our previous studies demonstrated that chronic IH could cause aggravated LVEF. Besides, higer concentations of ghrelin could increase the NO secretion and cell viability of endothelial cells expoture to hypoxia.We developed AMI rats model with with concomitant IH and EPCs model response to IH, then treat rats and EPCs with ghrelin and specific inhibitor of GHSR1a-PI3K/eNOS or mTOR. We’re interested in investigating whether exogenous Ghrelin can improve the angiogenic response and cardiac function in an IH rat model following ligation of left anterior descending coronary artery, via activation of bone marrow EPCs mobilization. We also investigate the role of the GHSR1a-PI3K pathway in relation to EPCs viability, migration and tube formation, using the technology of cell biology, molecular biology, flowcytometry, transwell migration assay and tube formation assay. Then testify the hypothesis of the therapeutic potential of Ghrelin for ameliorating the impaired angiogenesis and improving cardiac function in IH injury and infarcted rat models, which provides supporting evidence for the potential therapeutic application of ghrelin in the prevention and treatment of HFrEF caused by AMI with concomitant IH.

阻塞性睡眠呼吸暂停常合并冠心病，与急性心肌梗死（AMI）相关；间歇性低氧（IH）致内皮损伤在其中起关键作用。伴有LVEF降低的AMI存在内皮祖细胞（EPCs）动员不足，血管新生及心脏修复受限，进而致AMI后心功能恶化的问题。但AMI合并IH时，是否存在该问题，目前尚无文献报道。伴LVEF降低的AMI患者Ghrelin水平显著偏低，外源性Ghrelin可改善大鼠AMI后心功能。前期已发现慢性IH可引起大鼠LVEF显著降低；较高浓度的Ghrelin可增加IH内皮细胞上清中NO分泌，改善细胞活性。本研究在建立IH合并AMI动物模型和IH细胞模型后予Ghrelin及通路阻断剂干预，运用细胞与分子生物学、流式细胞仪、Transwell迁移实验、小管形成实验等技术，探讨Grelin对EPCs的动员及IH大鼠AMI后的血管新生与心功能的影响及其信号通路；这对IH合并AMI致HFrEF的防治具有重要意义。

阻塞性睡眠呼吸暂停常合并冠心病，与急性心肌梗死（AMI）相关；间歇性低氧（IH）致内皮损伤在其中起关键作用。伴LVEF减低的AMI患者Ghrelin水平显著偏低，外源性Ghrelin可改善大鼠AMI后心功能。前期已发现慢性IH可引起大鼠LVEF显著降低，较高浓度的Ghrelin可增加低氧内皮细胞上清中NO分泌，改善细胞活性。本研究在建立IH合并AMI动物模型和IH细胞模型后予Ghrelin及通路阻断剂干预，运用细胞与分子生物学、Transwell迁移实验、小管形成实验等技术，探讨Ghrelin对内皮祖细胞的动员及IH大鼠AMI后的血管新生与心功能的影响及其信号通路。.（1）研究动物水平结果提示Ghrelin对间歇性低氧大鼠心梗后2周、4周心功能的恶化有改善作用，增加梗死周边室壁质量，缩小梗死范围。为后续的生物工程及靶向治疗心肌梗死提供理论基础，具有临床应用转化价值。（2）研究改进的间歇性低氧小动物实验舱已申报发明专利，目前获得相关实用新型专利。该装置模拟OSAHS反复低氧的病理生理改变，对睡眠呼吸暂停合并心脑血管疾病防治具有重要意义，有助于确立新的治疗靶点，具有重要的理论意义和应用价值。