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Child's Nervous System
Published in: Child's Nervous System 5/2019

01-05-2019 | Original Article

Panobinostat, a histone deacetylase inhibitor, rescues the angiogenic potential of endothelial colony-forming cells in moyamoya disease

Authors: Anshika Jangra, Seung Ah Choi, Eun Jung Koh, Youn Joo Moon, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Seung-Ki Kim

Published in: Child's Nervous System | Issue 5/2019

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Abstract

Purpose

Moyamoya disease (MMD) is one of the most common causes of pediatric stroke. We found defective angiogenic function and downregulation of retinaldehyde dehydrogenase 2 (RALDH2) in MMD endothelial colony-forming cells (ECFCs). Downregulation of RALDH2 mRNA was caused by decreased binding of acetyl-histone H3 (Ac-H3) to the RALDH2 promoter. In this study, we evaluated the feasibility of using a histone deacetylase (HDAC) inhibitor, panobinostat, to upregulate RALDH2 expression and restore the angiogenic potential of MMD ECFCs.

Methods

ECFCs from healthy normal controls and patients with MMD were isolated and characterized. After panobinostat treatment, western blot, tube formation, and chromatin immunoprecipitation (ChIP) assays were conducted in vitro. A matrigel plug assay was performed in vivo.

Results

Panobinostat increased the levels of Ac-H3 and Ac-H4 in both normal and MMD ECFCs but was much more effective in MMD ECFCs. Increased expression of RALDH2 by panobinostat was observed only in MMD ECFCs. Panobinostat increased the tube formation of both normal and MMD ECFCs in vitro and in vivo, but the effect was greater with MMD ECFCs.

Conclusions

We demonstrated that panobinostat increases the angiogenic ability of MMD ECFCs by regulating RALDH2 acetylation. Our results suggest that panobinostat might be a potent therapeutic option for MMD patients.
Literature
1.
2.
Ismail I, Al-Khafaji K, Mutyala M, Aggarwal S, Al-Khafaji N, Kovacs D, Khosla S, Arora R (2015) “Smoke in the air”: a rare cerebrovascular cause of neurological signs and symptoms in a young adult. J Community Hosp Intern Med Perspect 5:27664CrossRefPubMed
3.
4.
Rafat N, Beck G, Pena-Tapia PG, Schmiedek P, Vajkoczy P (2009) Increased levels of circulating endothelial progenitor cells in patients with moyamoya disease. Stroke 40:432–438CrossRefPubMed
5.
Yamashita M, Oka K, Tanaka K (1983) Histopathology of the brain vascular network in moyamoya disease. Stroke 14:50–58CrossRefPubMed
6.
Kim JH, Jung JH, Phi JH, Kang HS, Kim JE, Chae JH, Kim SJ, Kim YH, Kim YY, Cho BK, Wang KC, Kim SK (2010) Decreased level and defective function of circulating endothelial progenitor cells in children with moyamoya disease. J Neurosci Res 88:510–518PubMed
7.
Lee JY, Moon YJ, Lee HO, Park AK, Choi SA, Wang KC, Han JW, Joung JG, Kang HS, Kim JE, Phi JH, Park WY, Kim SK (2015) Deregulation of retinaldehyde dehydrogenase 2 leads to defective angiogenic function of endothelial colony-forming cells in pediatric moyamoya disease. Arterioscler Thromb Vasc Biol 35:1670–1677CrossRefPubMed
8.
Fraineau S, Palii CG, Allan DS, Brand M (2015) Epigenetic regulation of endothelial-cell-mediated vascular repair. FEBS J 282:1605–1629CrossRefPubMed
9.
Fraineau S, Palii CG, McNeill B, Ritso M, Shelley WC, Prasain N, Chu A, Vion E, Rieck K, Nilufar S, Perkins TJ, Rudnicki MA, Allan DS, Yoder MC, Suuronen EJ, Brand M (2017) Epigenetic activation of pro-angiogenic signaling pathways in human endothelial progenitors increases vasculogenesis. Stem Cell Rep 9:1573–1587CrossRef
10.
Prasain N, Meador JL, Yoder MC (2012) Phenotypic and functional characterization of endothelial colony forming cells derived from human umbilical cord blood. J Vis Exp
11.
Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241CrossRefPubMed
12.
Javed MJ, Mead LE, Prater D, Bessler WK, Foster D, Case J, Goebel WS, Yoder MC, Haneline LS, Ingram DA (2008) Endothelial colony forming cells and mesenchymal stem cells are enriched at different gestational ages in human umbilical cord blood. Pediatr Res 64:68–73CrossRefPubMed
13.
Seo YJ, Kang Y, Muench L, Reid A, Caesar S, Jean L, Wagner F, Holson E, Haggarty SJ, Weiss P, King P, Carter P, Volkow ND, Fowler JS, Hooker JM, Kim SW (2014) Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors. ACS Chem Neurosci 5:588–596CrossRefPubMedPubMedCentral
14.
Fischer A, Sananbenesi F, Mungenast A, Tsai LH (2010) Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 31:605–617CrossRefPubMed
15.
Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, Sanni T, Atadja P, Pili R (2006) Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 12:634–642CrossRefPubMed
16.
17.
Joshi P, Greco TM, Guise AJ, Luo Y, Yu F, Nesvizhskii AI, Cristea IM (2013) The functional interactome landscape of the human histone deacetylase family. Mol Syst Biol 9:672CrossRefPubMedPubMedCentral
18.
Lee YE, Choi SA, Kwack PA, Kim HJ, Kim IH, Wang KC, Phi JH, Lee JY, Chong S, Park SH, Park KD, Hwang DW, Joo KM, Kim SK (2017) Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor. Neuro-Oncology 19:1079–1087CrossRefPubMedPubMedCentral
19.
Lee C, Lee J, Choi SA, Kim SK, Wang KC, Park SH, Kim SH, Lee JY, Phi JH (2018) M1 macrophage recruitment correlates with worse outcome in SHH medulloblastomas. BMC Cancer 18:535CrossRefPubMedPubMedCentral
20.
Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, Zhao K (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 40:897–903CrossRefPubMedPubMedCentral
21.
Karlic R, Chung HR, Lasserre J, Vlahovicek K, Vingron M (2010) Histone modification levels are predictive for gene expression. Proc Natl Acad Sci U S A 107:2926–2931CrossRefPubMedPubMedCentral
22.
Eckschlager T, Plch J, Stiborova M, Hrabeta J (2017) Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci 18
23.
Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784CrossRefPubMed
24.
Kuo MH, Allis CD (1998) Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 20:615–626CrossRefPubMed
25.
Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, Blacher S, Verdin E, Foidart JM, Nusgens BV, Castronovo V (2002) Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21:427–436CrossRefPubMed
26.
Rossig L, Li H, Fisslthaler B, Urbich C, Fleming I, Forstermann U, Zeiher AM, Dimmeler S (2002) Inhibitors of histone deacetylation downregulate the expression of endothelial nitric oxide synthase and compromise endothelial cell function in vasorelaxation and angiogenesis. Circ Res 91:837–844CrossRefPubMed
27.
Mottet D, Bellahcene A, Pirotte S, Waltregny D, Deroanne C, Lamour V, Lidereau R, Castronovo V (2007) Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ Res 101:1237–1246CrossRefPubMed
28.
Bapat SA (2013) Epigenetic regulation of cancer stem cell gene expression. Subcell Biochem 61:419–434CrossRefPubMed
29.
Bouvard C, Gafsou B, Dizier B, Galy-Fauroux I, Lokajczyk A, Boisson-Vidal C, Fischer AM, Helley D (2010) Alpha6-integrin subunit plays a major role in the proangiogenic properties of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 30:1569–1575CrossRefPubMed
30.
Palii CG, Vulesevic B, Fraineau S, Pranckeviciene E, Griffith AJ, Chu A, Faralli H, Li Y, McNeill B, Sun J, Perkins TJ, Dilworth FJ, Perez-Iratxeta C, Suuronen EJ, Allan DS, Brand M (2014) Trichostatin A enhances vascular repair by injected human endothelial progenitors through increasing the expression of TAL1-dependent genes. Cell Stem Cell 14:644–657CrossRefPubMed
Metadata
Title
Panobinostat, a histone deacetylase inhibitor, rescues the angiogenic potential of endothelial colony-forming cells in moyamoya disease
Authors
Anshika Jangra
Seung Ah Choi
Eun Jung Koh
Youn Joo Moon
Kyu-Chang Wang
Ji Hoon Phi
Ji Yeoun Lee
Seung-Ki Kim
Publication date
01-05-2019
Publisher
Springer Berlin Heidelberg
Published in
Child's Nervous System / Issue 5/2019
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI
https://doi.org/10.1007/s00381-019-04099-y

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