Int6-eIF3e Silencing Promotes Functional Blood Vessel Outgrowth and Enhances wound.pdf

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Int6-eIF3e Silencing Promotes Functional Blood Vessel Outgrowth and Enhances wound.pdf

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Int6-eIF3e Silencing Promotes Functional Blood Vessel Outgrowth and Enhances wound

Molecular Cardiology Int6/eIF3e Silencing Promotes Functional Blood Vessel Outgrowth and Enhances Wound Healing by Upregulating Hypoxia-Induced Factor 2 Expression Li Chen, PhD; Alexander Endler, PhD; Kazuyo Uchida, BS; Shin-ichiro Horiguchi, MD; Yoshihito Morizane, PhD; Osamu Iijima, PhD; Masakazu Toi, MD, PhD; Futoshi Shibasaki, MD, PhD Background—We previously identified INT6/eIF3e as a novel regulator of hypoxia-inducible factor 2 (HIF2) activity. Small interfering RNA (siRNA)–Int6 adequately stabilized HIF2, even under normoxic conditions, and thereby enhanced the expression of several angiogenic factors in vitro, suggesting that siRNA-Int6 may induce angiogenesis in vivo. Methods and Results—We demonstrated a 6- to 8-fold enhanced formation of normal arteries and veins in the subcutaneous regions of adult mice 5 days after a single siRNA-Int6 application. Subcutaneous fibroblasts were identified as the major source of secreted angiogenic factors that led to the formation of functional vessels during Int6 silencing. Fibroblasts transfected ex vivo with siRNA-Int6 induced potent neoangiogenesis when transplanted into a subcutaneous region of nude mice. Application of siRNA-Int6 promoted neoangiogenesis in the area surrounding the injury in wound healing models, including genetically diabetic mice, thereby accelerating the closure of the injury. HIF2 accumulation caused by siRNA-Int6 was confirmed as the unequivocal cause of the angiogenesis by an in vivo angiogenesis assay. Further analysis of the Int6 silencing–induced neoangiogenesis revealed that a negative feedback regulation of HIF2 stability was caused by HIF2-induced transcription of Int6 via hypoxia-response elements in its promoter. Thus, siRNA-Int6 temporarily facilitates an accumulation of HIF2 protein, leading to hypoxia-independent transcription of angiogenic factors and concomitant neoangiogenesis. Conclusions—We suggest that the pathway involving INT6/HIF2 acts as a hypoxia-independent ma