PMID- 31101061 OWN - NLM STAT- MEDLINE DCOM- 20191224 LR - 20200225 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 16 IP - 1 DP - 2019 May 17 TI - HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice. PG - 103 LID - 10.1186/s12974-019-1495-3 [doi] LID - 103 AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic dysfunction characterized by progressive insulin resistance and hyperglycaemia. Increased blood-brain barrier (BBB) permeability is a critical neurovascular complication of T2DM that adversely affects the central nervous system homeostasis and function. Histone deacetylase 3 (HDAC3) has been reported to be elevated in T2DM animals and may promote neuroinflammation; however, its involvement in the BBB permeability of T2DM has not been investigated. In this study, we tested our hypothesis that HDAC3 expression and activity are increased in the T2DM mouse brain. Inhibition of HDAC3 may ameliorate T2DM-induced BBB permeability through Nrf2 activation. METHODS: T2DM (db/db, leptin receptor-deficient), genetic non-hyperglycemic control (db/+), and wild-type male mice at the age of 16 weeks were used in this study. HDAC3 expression and activity, Nrf2 activation, and BBB permeability and junction protein expression were examined. The effects of HDAC3 activity on BBB permeability were tested using highly selective HDAC3 inhibitor RGFP966. In primary cultured human brain microvascular endothelial cells (HBMEC), hyperglycemia (25 mM glucose) plus interleukin 1 beta (20 ng/ml) (HG-IL1beta) served as T2DM insult in vitro. The effects of HDAC3 on transendothelial permeability were investigated by FITC-Dextran leakage and trans-endothelial electrical resistance, and the underlying molecular mechanisms were investigated using Western blot, q-PCR, co-immunoprecipitation, and immunocytochemistry for junction protein expression, miR-200a/Keap1/Nrf2 pathway regulation. RESULTS: HDAC3 expression and activity were significantly increased in the hippocampus and cortex of db/db mice. Specific HDAC3 inhibition significantly ameliorated BBB permeability and junction protein downregulation in db/db mice. In cultured HBMEC, HG-IL1beta insult significantly increased transendothelial permeability and reduced junction protein expression. HDAC3 inhibition significantly attenuated the transendothelial permeability and junction protein downregulation. Moreover, we demonstrated the underlying mechanism was at least in part attributed by HDAC3 inhibition-mediated miR-200a/Keap1/Nrf2 signaling pathway and downstream targeting junction protein expression in T2DM db/db mice. CONCLUSIONS: Our experimental results show that HDAC3 might be a new therapeutic target for BBB damage in T2DM. FAU - Zhao, Qiuchen AU - Zhao Q AD - Department of Neurology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Rd, Nanjing, 210008, Jiangsu, China. AD - Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, Boston, MA, 02129, USA. FAU - Zhang, Fang AU - Zhang F AD - Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. AD - Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, Boston, MA, 02129, USA. FAU - Yu, Zhanyang AU - Yu Z AD - Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, Boston, MA, 02129, USA. FAU - Guo, Shuzhen AU - Guo S AD - Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, Boston, MA, 02129, USA. FAU - Liu, Ning AU - Liu N AD - Department of Neurology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Rd, Nanjing, 210008, Jiangsu, China. AD - The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. FAU - Jiang, Yinghua AU - Jiang Y AD - Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, Boston, MA, 02129, USA. FAU - Lo, Eng H AU - Lo EH AD - Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, Boston, MA, 02129, USA. FAU - Xu, Yun AU - Xu Y AD - Department of Neurology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Rd, Nanjing, 210008, Jiangsu, China. xuyun20042001@aliyun.com. FAU - Wang, Xiaoying AU - Wang X AD - Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, Boston, MA, 02129, USA. wangxi@helix.mgh.harvard.edu. LA - eng GR - 81630028/National Natural Science Foundation of China/ GR - BE2016610/Key Research and Development Program of Jiangsu Province of China/ GR - 2016YFC1300504/National Key Research and Development Program of China/ GR - ZDXKA2016020/Jiangsu Province Key Medical Discipline/ PT - Journal Article DEP - 20190517 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Acrylamides) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Phenylenediamines) RN - 0 (RGFP966) RN - EC 3.5.1.98 (Histone Deacetylases) RN - EC 3.5.1.98 (histone deacetylase 3) SB - IM MH - Acrylamides/pharmacology/therapeutic use MH - Animals MH - Blood-Brain Barrier/drug effects/*metabolism MH - Cell Line MH - Diabetes Mellitus, Experimental/drug therapy/metabolism MH - Diabetes Mellitus, Type 2/*drug therapy/*metabolism MH - Endothelial Cells/drug effects/metabolism MH - Histone Deacetylase Inhibitors/pharmacology/*therapeutic use MH - Histone Deacetylases/*metabolism MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - NF-E2-Related Factor 2/*metabolism MH - Permeability/drug effects MH - Phenylenediamines/pharmacology/therapeutic use PMC - PMC6525453 OTO - NOTNLM OT - Blood-brain barrier (BBB) OT - Diabetes OT - Histone deacetylase 3 (HDAC3) OT - Hyperglycemia OT - Interleukin 1 beta (IL1beta) OT - Neuroinflammation OT - Nuclear factor-E2-related factor 2 (Nrf2) COIS- The authors declare that they have no competing interests. EDAT- 2019/05/19 06:00 MHDA- 2019/12/25 06:00 PMCR- 2019/05/17 CRDT- 2019/05/19 06:00 PHST- 2018/11/22 00:00 [received] PHST- 2019/04/30 00:00 [accepted] PHST- 2019/05/19 06:00 [entrez] PHST- 2019/05/19 06:00 [pubmed] PHST- 2019/12/25 06:00 [medline] PHST- 2019/05/17 00:00 [pmc-release] AID - 10.1186/s12974-019-1495-3 [pii] AID - 1495 [pii] AID - 10.1186/s12974-019-1495-3 [doi] PST - epublish SO - J Neuroinflammation. 2019 May 17;16(1):103. doi: 10.1186/s12974-019-1495-3.