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

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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.

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Funding

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).

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Author notes

  1. Anshika Jangra and Seung Ah Choi contributed equally to this work.

Authors and Affiliations

  1. Division of Pediatric Neurosurgery, Seoul Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea

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

  2. Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea

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

  3. Department of Anatomy, Seoul National University College of Medicine, Seoul, South Korea

    Ji Yeoun Lee

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  1. Anshika Jangra
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  2. Seung Ah Choi
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  3. Eun Jung Koh
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Corresponding author

Correspondence to Seung-Ki Kim.

Ethics declarations

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).

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Jangra, A., Choi, S.A., Koh, E.J. et al. Panobinostat, a histone deacetylase inhibitor, rescues the angiogenic potential of endothelial colony-forming cells in moyamoya disease. Childs Nerv Syst 35, 823–831 (2019). https://doi.org/10.1007/s00381-019-04099-y

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