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Child's Nervous System

, Volume 35, Issue 5, pp 823–831 | Cite as

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

  • Anshika Jangra
  • Seung Ah Choi
  • Eun Jung Koh
  • Youn Joo Moon
  • Kyu-Chang Wang
  • Ji Hoon Phi
  • Ji Yeoun Lee
  • Seung-Ki KimEmail author
Original Article
  • 68 Downloads

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.

Keywords

Moyamoya disease Endothelial colony-forming cells HDAC inhibitor 

Notes

Funding information

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI12C0066).

Compliance with ethical standards

Blood samples from MMD patients (N = 5) and healthy controls (N = 5) were obtained (Table 1) with informed consent under the Institutional Review Board (IRB) of the Seoul National University Hospital (SNUH IRB approval number 1610-108-801).

Conflict of interest

The authors have no financial conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Anshika Jangra
    • 1
    • 2
  • Seung Ah Choi
    • 1
    • 2
  • Eun Jung Koh
    • 1
    • 2
  • Youn Joo Moon
    • 1
    • 2
  • Kyu-Chang Wang
    • 1
    • 2
  • Ji Hoon Phi
    • 1
    • 2
  • Ji Yeoun Lee
    • 1
    • 2
    • 3
  • Seung-Ki Kim
    • 1
    • 2
    Email author
  1. 1.Division of Pediatric NeurosurgerySeoul Pediatric Clinical Neuroscience Center, Seoul National University Children’s HospitalSeoulRepublic of Korea
  2. 2.Department of NeurosurgerySeoul National University Hospital, Seoul National University College of MedicineSeoulSouth Korea
  3. 3.Department of AnatomySeoul National University College of MedicineSeoulSouth Korea

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