Silencing of Int6 Promotes Recovery of Blood Perfusion after Limb Ischemia via Stabilizing Hypoxia-Inducible Factor 2α

Int6 沉默通过稳定缺氧诱导因子 2α 促进肢体缺血后血液灌注的恢复

• 批准号: 20591513
• 负责人: KIMURA Hideo
• 金额: $ 3万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591513/
• 关键词: 血管外外科一般; 血管新生; 低酸素応答因子; 乳癌抑制遺伝子; 低酸素誘導因子; 血管再生; RNA干渉

Hypoxia-inducible factors (HIFs) are the key regulators of hypoxia-responding genes. In particular, the HIF-2α plays an essential role in vascular remodeling, leading to mature angiogenesis by transcribing several angiogenic factors. The aim of current study is to test the hypothesis that silencing of Int6 and concomitant HIF-2α stabilization may enhance the recovery of blood flow in tissue ischemia. Analysis of the effect of Int6 silencing in cultured muscle cells implied that silencing of Int6 led to up-regulation of several genes corresponding to angiogenic proteins, including basic fibroblast growth factor and platelet-derived growth factor-B through induction and stabilization of HIF-2α. Moreover, tube formation analysis of endothelial cells revealed an increase in paracrine response to INT6-silenced muscle cells. In mouse models of hindlimb ischemia, intramuscular injection of small interfering RNA plasmid designed to inhibit Int6 led to significantly enhanced perfusion and functional recovery of damaged tissues. Int6 silencing in muscle leads to enhanced recovery of blood flow in ischemic limb. Int6 may serve as a valuable therapeutic target to control angiogenesis in ischemic diseases.

低氧诱导因子（Hypoxia-inducible factors，HIF）是低氧应答基因的关键调控因子。特别是，HIF-2α在血管重塑中起重要作用，通过转录几种血管生成因子导致成熟的血管生成。本研究的目的是验证Int 6沉默和伴随的HIF-2α稳定可能增强组织缺血中血流恢复的假设。对Int 6沉默在培养的肌肉细胞中的作用的分析表明，Int 6的沉默通过诱导和稳定HIF-2α导致与血管生成蛋白相对应的几个基因的上调，包括碱性成纤维细胞生长因子和血小板衍生生长因子-B。此外，内皮细胞的管形成分析揭示了对INT 6沉默的肌细胞的旁分泌反应的增加。在小鼠后肢缺血模型中，肌肉注射设计用于抑制Int 6的小干扰RNA质粒导致受损组织的灌注和功能恢复显著增强。肌肉中的Int 6沉默导致缺血肢体中血流的恢复增强。Int 6可能作为一个有价值的治疗靶点来控制缺血性疾病中的血管生成。

项目成果

マウス下肢虚血モデルにおけるInt6抑制による下肢血流の改善-低酸素応答因子HIF-2αの誘導を介した血管新生の可能性

通过抑制小鼠下肢缺血模型中的 Int6 改善下肢血流量 - 通过诱导缺氧反应因子 HIF-2α 促进血管生成的可能性

• 发表时间: 2008
• 作者: 橋本拓弥;ら
• 通讯作者: ら

マウス下肢虚血モデルにおけるInt6抑制による下肢血流の改善

抑制Int6改善小鼠下肢缺血模型下肢血流

• 发表时间: 2008
• 作者: 橋本拓弥;木村秀生;他
• 通讯作者: 他