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

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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.