Vascular Program, Institute for Cell Engineering and Departments of Medicine, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10504-9. doi: 10.1073/pnas.1208314109. Epub 2012 Jun 13.
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 hypoxia/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-1α 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 acriflavine) 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.
当心肌灌注长时间中断时，就会发生梗塞。当心脏随后经历长时间的缺血发作时，短暂的缺血和再灌注 episodes 会保护组织免受损伤，这种现象称为缺血预处理 (IPC)。缺氧诱导因子 1 (HIF-1) 是一种转录因子，介导缺氧/缺血的适应性反应，是 IPC 的必需条件。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 Tie2(+)谱系细胞（包括骨髓 (BM) 和血管内皮细胞）中敲除 HIF-1α 或 HIF-1β 的小鼠与对照同窝仔鼠相比。心脏接受 30 分钟缺血和 120 分钟再灌注，无论是作为离体 Langendorff 制剂还是通过左前降支的原位闭塞。IPC 刺激由两个 5 分钟缺血和 5 分钟再灌注循环组成。Tie2(+)谱系细胞中缺乏 HIF-1α 或 HIF-1β 的小鼠完全缺乏 IPC 诱导的保护，而腺苷输注则诱导显著的保护。在 Langendorff 灌注前 4 小时用 HIF-1 抑制剂（地高辛或吖啶黄素）处理小鼠，或在 IPC 前立即将吖啶黄素直接注入灌流液中，均可导致 IPC 丧失。我们得出结论，内皮细胞中的 HIF-1 活性是急性 IPC 的必需条件。HIF-1α 和 HIF-1β 亚基的表达和二聚化是必需的，这表明尽管反应是急性的，但异二聚体作为转录激活剂起作用。
