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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning
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Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning

机译:缺氧诱导因子1在内皮细胞中的转录活性是缺血预适应诱导的急性期心脏保护所必需的

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摘要

Infarction occurs when myocardial perfusion is interrupted for prolonged periods of time. Short episodes of ischemia and reperfusion protect against tissue injury when the heart is subjected to a subsequent prolonged ischemic episode, a phenomenon known as ischemic preconditioning (IPC). Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to hyp-oxia/ischemia and is required for IPC. In this study, we performed a cellular and molecular characterization of the role of HIF-1 in IPC. We analyzed mice with knockout of HIF-1 α or HIF-1β in Tie2~+ lineage cells, which include bone marrow (BM) and vascular endothelial cells, compared with control littermates. Hearts were subjected to 30 min of ischemia and 120 min of reperfusion, either as ex vivo Langendorff preparations or by in situ occlusion of the left anterior descending artery. The IPC stimulus consisted of two cycles of 5-min ischemia and 5-min reperfusion. Mice lacking HIF-1α or HIF-1β in Tie2~+ lineage cells showed complete absence of protection induced by IPC, whereas significant protection was induced, by adenosine infusion. Treatment of mice with a HIF-1 inhibitor (digoxin or acri-flavine) 4 h before Langendorff perfusion resulted in loss of IPC, as did administration of acriflavine directly into the perfusate immediately before IPC. We conclude that HIF-1 activity in endothelial cells is required for acute IPC. Expression and dimerization of the HIF-1α and HIF-1β subunits is required, suggesting that the heterodimer is functioning as a transcriptional activator, despite the acute nature of the response.
机译:长时间中断心肌灌注会发生梗塞。当心脏经受随后的长时间缺血性发作时,短暂的缺血和再灌注发作可防止组织损伤,这种现象称为缺血性预处理(IPC)。缺氧诱导因子1(HIF-1)是一种转录因子,介导对缺氧/缺血的适应性反应,是IPC所必需的。在这项研究中,我们对HIF-1在IPC中的作用进行了细胞和分子表征。我们分析了与对照同窝幼仔相比,Tie2〜+系细胞(包括骨髓(BM)和血管内皮细胞)中具有HIF-1α或HIF-1β基因敲除的小鼠。作为离体Langendorff制剂或通过左前降支的原位闭塞,对心脏进行30分钟的缺血和120分钟的再灌注。 IPC刺激由两个5分钟的缺血和5分钟的再灌注周期组成。在Tie2〜+谱系细胞中缺乏HIF-1α或HIF-1β的小鼠表现出完全没有IPC诱导的保护作用,而腺苷输注则诱导了明显的保护作用。在Langendorff灌注前4小时,用HIF-1抑制剂(地高辛或Acri-flavine)处理小鼠会导致IPC丧失,而在刚于IPC之前将Acriflavine直接注入灌流液中也会导致IPC丧失。我们得出结论,急性IPC需要内皮细胞中的HIF-1活性。 HIF-1α和HIF-1β亚基的表达和二聚化是必需的,这表明尽管反应的急性性质,异二聚体仍起着转录激活剂的作用。

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  • 作者单位

    Vascular Program, Institute for Cell Engineering and Departments of The Johns Hopkins University School of Medicine, Baltimore, MD 21205, Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Vascular Program, Institute for Cell Engineering and Departments of The Johns Hopkins University School of Medicine, Baltimore, MD 21205, Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Vascular Program, Institute for Cell Engineering and Departments of The Johns Hopkins University School of Medicine, Baltimore, MD 21205, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

    Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20814;

    Vascular Program, Institute for Cell Engineering and Departments of The Johns Hopkins University School of Medicine, Baltimore, MD 21205, Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    CD39; CD73; coronary artery disease; myocardial infarction; oxygen;

    机译:CD39;CD73;冠状动脉疾病;心肌梗塞;氧;

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