Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis via Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

JH Kim, KS Lee, DK Lee, J Kim, SN Kwak… - Antioxidants & redox …, 2014 - liebertpub.com
JH Kim, KS Lee, DK Lee, J Kim, SN Kwak, KS Ha, J Choe, MH Won, BR Cho, D Jeoung
Antioxidants & redox signaling, 2014liebertpub.com
Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate
angiogenesis and vascular function. In this study, we investigated a new functional role of
new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for
regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF)
expression. Results: We found that hypoxia induced miR-101, which binds to the 3′
untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2 …
Abstract
Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate angiogenesis and vascular function. In this study, we investigated a new functional role of new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) expression. Results: We found that hypoxia induced miR-101, which binds to the 3′untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2-related factor 2 (Nrf2) via inhibition of the proteasomal degradation pathway. miR-101 overexpression promoted Nrf2 nuclear accumulation, which was accompanied with increases in HO-1 induction, VEGF expression, and endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. The elevated NO-induced S-nitrosylation of Kelch-like ECH-associated protein 1 and subsequent induction of Nrf2-dependent HO-1 lead to further elevation of VEGF production via a positive feedback loop between the Nrf2/HO-1 and VEGF/eNOS axes. Moreover, miR-101 promoted angiogenic signals and angiogenesis both in vitro and in vivo, and these events were attenuated by inhibiting the biological activity of HO-1, VEGF, or eNOS. Moreover, these effects were also observed in aortic rings from HO-1+/− and eNOS−/− mice. Local overexpression of miR-101 improved therapeutic angiogenesis and perfusion recovery in the ischemic mouse hindlimb, whereas antagomiR-101 diminished regional blood flow. Innovation: Hypoxia-responsive miR-101 stimulates angiogenesis by activating the HO-1/VEGF/eNOS axis via Cul3 targeting. Thus, miR-101 is a novel angiomir. Conclusion: Our results provide new mechanistic insights into a functional role of miR-101 as a potential therapeutic target in angiogenesis and vascular remodeling. Antioxid. Redox Signal. 21, 2469–2482.
Mary Ann Liebert