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Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase

The topical application of minoxidil may achieve millimolar concentrations in the skin. We investigated whether millimolar minoxidil could induce vascular endothelial growth factor (VEGF), a possible effector for minoxidil-mediated hair growth, and how it occurred at the molecular level. Cell-based...

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Autores principales: Yum, Soohwan, Jeong, Seongkeun, Kim, Dohoon, Lee, Sunyoung, Kim, Wooseong, Yoo, Jin-Wook, Kim, Jung-Ae, Kwon, Oh Sang, Kim, Dae-Duk, Min, Do Sik, Jung, Yunjin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796003/
https://www.ncbi.nlm.nih.gov/pubmed/29295567
http://dx.doi.org/10.3390/ijms19010053
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author Yum, Soohwan
Jeong, Seongkeun
Kim, Dohoon
Lee, Sunyoung
Kim, Wooseong
Yoo, Jin-Wook
Kim, Jung-Ae
Kwon, Oh Sang
Kim, Dae-Duk
Min, Do Sik
Jung, Yunjin
author_facet Yum, Soohwan
Jeong, Seongkeun
Kim, Dohoon
Lee, Sunyoung
Kim, Wooseong
Yoo, Jin-Wook
Kim, Jung-Ae
Kwon, Oh Sang
Kim, Dae-Duk
Min, Do Sik
Jung, Yunjin
author_sort Yum, Soohwan
collection PubMed
description The topical application of minoxidil may achieve millimolar concentrations in the skin. We investigated whether millimolar minoxidil could induce vascular endothelial growth factor (VEGF), a possible effector for minoxidil-mediated hair growth, and how it occurred at the molecular level. Cell-based experiments were performed to investigate a molecular mechanism underlying the millimolar minoxidil induction of VEGF. The inhibitory effect of minoxidil on hypoxia-inducible factor (HIF) prolyl hydroxylase-2 (PHD-2) was tested by an in vitro von Hippel–Lindau protein (VHL) binding assay. To examine the angiogenic potential of millimolar minoxidil, a chorioallantoic membrane (CAM) assay was used. In human keratinocytes and dermal papilla cells, millimolar minoxidil increased the secretion of VEGF, which was not attenuated by a specific adenosine receptor antagonist that inhibits the micromolar minoxidil induction of VEGF. Millimolar minoxidil induced hypoxia-inducible factor-1α (HIF-1α), and the induction of VEGF was dependent on HIF-1. Moreover, minoxidil applied to the dorsal area of mice increased HIF-1α and VEGF in the skin. In an in vitro VHL binding assay, minoxidil directly inhibited PHD-2, thus preventing the hydroxylation of cellular HIF-1α and VHL-dependent proteasome degradation and resulting in the stabilization of HIF-1α protein. Minoxidil inhibition of PHD-2 was reversed by ascorbate, a cofactor of PHD-2, and the minoxidil induction of cellular HIF-1α was abrogated by the cofactor. Millimolar minoxidil promoted angiogenesis in the CAM assay, an in vivo angiogenic test, and this was nullified by the specific inhibition of VEGF. Our data demonstrate that PHD may be the molecular target for millimolar minoxidil-mediated VEGF induction via HIF-1.
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spelling pubmed-57960032018-02-09 Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase Yum, Soohwan Jeong, Seongkeun Kim, Dohoon Lee, Sunyoung Kim, Wooseong Yoo, Jin-Wook Kim, Jung-Ae Kwon, Oh Sang Kim, Dae-Duk Min, Do Sik Jung, Yunjin Int J Mol Sci Article The topical application of minoxidil may achieve millimolar concentrations in the skin. We investigated whether millimolar minoxidil could induce vascular endothelial growth factor (VEGF), a possible effector for minoxidil-mediated hair growth, and how it occurred at the molecular level. Cell-based experiments were performed to investigate a molecular mechanism underlying the millimolar minoxidil induction of VEGF. The inhibitory effect of minoxidil on hypoxia-inducible factor (HIF) prolyl hydroxylase-2 (PHD-2) was tested by an in vitro von Hippel–Lindau protein (VHL) binding assay. To examine the angiogenic potential of millimolar minoxidil, a chorioallantoic membrane (CAM) assay was used. In human keratinocytes and dermal papilla cells, millimolar minoxidil increased the secretion of VEGF, which was not attenuated by a specific adenosine receptor antagonist that inhibits the micromolar minoxidil induction of VEGF. Millimolar minoxidil induced hypoxia-inducible factor-1α (HIF-1α), and the induction of VEGF was dependent on HIF-1. Moreover, minoxidil applied to the dorsal area of mice increased HIF-1α and VEGF in the skin. In an in vitro VHL binding assay, minoxidil directly inhibited PHD-2, thus preventing the hydroxylation of cellular HIF-1α and VHL-dependent proteasome degradation and resulting in the stabilization of HIF-1α protein. Minoxidil inhibition of PHD-2 was reversed by ascorbate, a cofactor of PHD-2, and the minoxidil induction of cellular HIF-1α was abrogated by the cofactor. Millimolar minoxidil promoted angiogenesis in the CAM assay, an in vivo angiogenic test, and this was nullified by the specific inhibition of VEGF. Our data demonstrate that PHD may be the molecular target for millimolar minoxidil-mediated VEGF induction via HIF-1. MDPI 2017-12-25 /pmc/articles/PMC5796003/ /pubmed/29295567 http://dx.doi.org/10.3390/ijms19010053 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yum, Soohwan
Jeong, Seongkeun
Kim, Dohoon
Lee, Sunyoung
Kim, Wooseong
Yoo, Jin-Wook
Kim, Jung-Ae
Kwon, Oh Sang
Kim, Dae-Duk
Min, Do Sik
Jung, Yunjin
Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase
title Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase
title_full Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase
title_fullStr Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase
title_full_unstemmed Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase
title_short Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase
title_sort minoxidil induction of vegf is mediated by inhibition of hif-prolyl hydroxylase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796003/
https://www.ncbi.nlm.nih.gov/pubmed/29295567
http://dx.doi.org/10.3390/ijms19010053
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