Silencing of Int6 Promotes Recovery of Blood Perfusion after Limb Ischemia via Stabilizing Hypoxia-Inducible Factor 2α
| Project/Area Number |
20591513
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KIMURA Hideo The University of Tokyo, 医学部附属病院, 助教 (60327070)
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| Co-Investigator(Kenkyū-buntansha) |
KOYAMA Hiroyuki 東京大学, 医学部附属病院, 特任准教授 (10241994)
MIYATA Tetsuro 東京大学, 医学部附属病院, 准教授 (70190791)
SHIGEMATSU Kunihiro 東京大学, 医学部附属病院, 講師 (20215966)
OKAMOTO Hiroyuki 東京大学, 医学部附属病院, 助教 (60348266)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2008: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | 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 |
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| Research Abstract |
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.
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Report
(4 results)
Research Products
(3 results)
