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HDAC 3 inhibition prevents oxygen glucose deprivation/reoxygenation‐induced transendothelial permeability by elevating PPAR γ activity in vitro
Author(s) -
Zhao Qiuchen,
Yu Zhanyang,
Zhang Fang,
Huang Lena,
Xing Changhong,
Liu Ning,
Xu Yun,
Wang Xiaoying
Publication year - 2019
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14619
Subject(s) - histone deacetylase , microbiology and biotechnology , acetylation , small interfering rna , peroxisome proliferator activated receptor , endothelial stem cell , receptor , chemistry , biology , in vitro , cancer research , biochemistry , histone , rna , gene
Histone deacetylase 3 ( HDAC 3), a member of class I HDAC , regulates a wide variety of normal and abnormal physiological functions. Recent experimental studies suggested that inhibition of HDAC 3 may increase acetylation of certain key signaling regulating proteins such as peroxisome proliferator‐activated receptor γ ( PPAR γ), which plays a crucial role in modulating cerebrovascular function and integrity. However, the role of HDAC 3 inhibition in cerebrovascular endothelium function under pathological condition has not been fully investigated. In this study, we tested the hypothesis that inhibition of HDAC 3 by RGFP 966, a highly selective HDAC 3 inhibitor, promotes PPAR γ activation by enhancing its protein acetylation, resulting in protection of oxygen glucose deprivation and reoxygenation ( OGD /R)‐induced increase of transendothelial cell permeability. In cultured primary human brain microvascular endothelial cells, our experimental results show that OGD /R increases transendothelial cell permeability and down‐regulates junction protein expression. While we also detected HDAC 3 activity increase and PPAR γ activity decline after OGD /R. However, treatment with RGFP 966 significantly attenuated the OGD /R‐induced increase of transendothelial cell permeability and down‐regulation of tight junction protein Claudin‐5. These effects were observed to be dependent on HDAC 3 activity inhibition‐mediated PPAR γ protein acetylation/activation. Lastly, HDAC 3 small interfering RNA mimics the protective effects of RGFP 966 on human brain microvascular endothelial cells. Taken together, our data indicate that HDAC 3 inhibition might comprise a new therapeutic target for reducing blood–brain barrier integrity disruption and vascular dysfunctions in neurological disorders.