Imperial College London
Alternate

ProfessorLanZhao

Faculty of Medicine, National Heart & Lung Institute

Professor of Experimental Medicine
 
 
 
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Contact

 

+44 (0)20 7594 6823l.zhao

 
 
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Location

 

531ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Chelladurai:2020:10.1038/s41598-020-69737-x,
author = {Chelladurai, P and Dabral, S and Basineni, SR and Chen, C-N and Schmoranzer, M and Bender, N and Feld, C and Noetzold, RR and Dobreva, G and Wilhelm, J and Jungblut, B and Zhao, L and Bauer, U-M and Seeger, W and Pullamsetti, SS},
doi = {10.1038/s41598-020-69737-x},
journal = {Scientific Reports},
pages = {1--20},
title = {Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension},
url = {http://dx.doi.org/10.1038/s41598-020-69737-x},
volume = {10},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circu
AU  - Chelladurai,P
AU  - Dabral,S
AU  - Basineni,SR
AU  - Chen,C-N
AU  - Schmoranzer,M
AU  - Bender,N
AU  - Feld,C
AU  - Noetzold,RR
AU  - Dobreva,G
AU  - Wilhelm,J
AU  - Jungblut,B
AU  - Zhao,L
AU  - Bauer,U-M
AU  - Seeger,W
AU  - Pullamsetti,SS
DO  - 10.1038/s41598-020-69737-x
EP  - 20
PY  - 2020///
SN  - 2045-2322
SP  - 1
TI  - Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension
T2  - Scientific Reports
UR  - http://dx.doi.org/10.1038/s41598-020-69737-x
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000559797100082&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.nature.com/articles/s41598-020-69737-x#Abs1
UR  - http://hdl.handle.net/10044/1/85270
VL  - 10
ER  -
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