HDAC3 inhibition prevents oxygen glucose deprivation/reoxygenation‐induced transendothelial permeability by elevating PPARγ activity in vitro. Issue 2 (3rd December 2018)

• Record Type: Journal Article
• Authors: Zhao, Qiuchen; Yu, Zhanyang; Zhang, Fang; Huang, Lena; Xing, Changhong; Liu, Ning; Xu, Yun; Wang, Xiaoying
• Is Part Of: Journal of neurochemistry. Volume 149:Issue 2(2019)
• Page Start: 298
• Page End: 310
• Publication Date: 2018-12-03
• Subjects: histone deacetylase 3 -- human brain microvascular endothelial cells -- oxygen glucose deprivation and reoxygenation -- peroxisome proliferator‐activated receptor γ -- RGFP966 -- transendothelial permeability; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14619
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Histone deacetylase 3 (HDAC3), a member of class I HDAC, regulates a wide variety of normal and abnormal physiological functions. Recent experimental studies suggested that inhibition of HDAC3 may increase acetylation of certain key signaling regulating proteins such as peroxisome proliferator‐activated receptor γ (PPARγ), which plays a crucial role in modulating cerebrovascular function and integrity. However, the role of HDAC3 inhibition in cerebrovascular endothelium function under pathological condition has not been fully investigated. In this study, we tested the hypothesis that inhibition of HDAC3 by RGFP966, a highly selective HDAC3 inhibitor, promotes PPARγ 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 HDAC3 activity increase and PPARγ activity decline after OGD/R. However, treatment with RGFP966 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 HDAC3 activity inhibition‐mediated PPARγ protein acetylation/activation. Lastly, HDAC3 small interfering RNA mimics the protective effects of RGFP966 on human brain microvascular endothelial cells. Taken together, our data indicate that HDAC3 inhibition might comprise a new therapeutic target for reducing blood–brain barrier integrity disruption and vascular dysfunctions in neurological disorders. Abstract : Increasing evidence support that histone hypoacetylation and transcriptional dysfunction are involved in blood–brain barrier (BBB) pathophysiology in ischemic stroke and other neurological disorders. In cultured primary human brain microvascular endothelial cells, OGD/R induces HDAC3 activity increase and PPARγ activity decline, ultimately leads to transendothelial cell permeability increase. Inhibition of HDAC3 by RGFP966 promotes PPARγ acetylation that results in its activity elevation, which attenuates the OGD/R‐induced transendothelial permeability increase, might be in part by rescuing OGD/R‐induced Claudin‐5 down‐regulation.