title: HDAC9 exacerbates endothelial injury in cerebral ischaemia/reperfusion injury.
abstract: Histone deacetylase (HDAC) 9, a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions, which is usually expressed at high levels in the brain and skeletal muscle. Although studies have highlighted the importance of HDAC-mediated epigenetic processes in the development of ischaemic stroke and very recent genome-wide association studies have identified a variant in HDAC9 associated with large-vessel ischemic stroke, the molecular events by which HDAC9 induces cerebral injury keep unclear. In this study, we found that HDAC9 was up-regulated in the ischaemic cerebral hemisphere after cerebral ischaemia/reperfusion (I/R) injury in rats and in vivo gene silencing of HDAC9 by recombinated lentivirus infection in the brain reduced cerebral injury in experimental stroke. We further demonstrated that HDAC9 contributed to oxygen-glucose deprivation-induced brain microvessel endothelial cell dysfunction as demonstrated by the increased inflammatory responses, cellular apoptosis and endothelial cell permeability dysfunction accompanied by reduced expression of tight-junction proteins. We further found that HDAC9 suppressed autophagy, which was associated with endothelial dysfunction. This study for the first time provides direct evidence that HDAC9 contributes to endothelial cell injury and demonstrates that HDAC9 is one of critical components of a signal transduction pathway that links cerebral injury to epigenetic modification in the brain.
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.|Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, China.
authors: Weichen
authors: W
authors: Shi
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Xinbing
authors: X
authors: Wei
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Ziying
authors: Z
authors: Wang
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Huirong
authors: H
authors: Han
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Yi
authors: Y
authors: Fu
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Jiang
authors: J
authors: Liu
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Yan
authors: Y
authors: Zhang
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Jian
authors: J
authors: Guo
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Chuanqiao
authors: C
authors: Dong
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Di
authors: D
authors: Zhou
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Quan
authors: Q
authors: Zhou
authors: Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, China.
authors: Yuxin
authors: Y
authors: Chen
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, China.
authors: Fan
authors: F
authors: Yi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001812:Blood-Brain Barrier / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000098:blood supply*; D002545:Brain Ischemia / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D002463:Cell Membrane Permeability; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D005947:Glucose / Q000172:deficiency; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D055806:Microvessels / Q000473:pathology; D010100:Oxygen; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015854:Up-Regulation
chemical_list: C552726:HDAC9 protein, rat; D006655:Histone Deacetylases; D005947:Glucose; D010100:Oxygen
keywords: autophagy; blood-brain barrier; gene therapy; histone deacetylase; ischaemic stroke