HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice

Journal of Neuroinflammation

Yun Xu¹  Qiuchen Zhao²  Ning Liu³  Xiaoying Wang⁴  Yinghua Jiang⁴  Zhanyang Yu⁴  Eng H. Lo⁴  Shuzhen Guo⁴  Fang Zhang⁵ 

[1] 0000 0001 2314 964X, grid.41156.37, Department of Neurology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Rd, 210008, Nanjing, Jiangsu, China;0000 0001 2314 964X, grid.41156.37, Department of Neurology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Rd, 210008, Nanjing, Jiangsu, China;0000 0004 0386 9924, grid.32224.35, Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, 02129, Boston, MA, USA;0000 0001 2314 964X, grid.41156.37, Department of Neurology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, 321 Zhongshan Rd, 210008, Nanjing, Jiangsu, China;grid.412719.8, The Third Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan, China;0000 0004 0386 9924, grid.32224.35, Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, 02129, Boston, MA, USA;0000 0004 1757 9434, grid.412645.0, Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 300052, Tianjin, China;0000 0004 0386 9924, grid.32224.35, Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 2401, Charlestown, 02129, Boston, MA, USA;

关键词: Neuroinflammation;    Histone deacetylase 3 (HDAC3);    Diabetes;    Blood-brain barrier (BBB);    Hyperglycemia;    Interleukin 1 beta (IL1β);    Nuclear factor-E2-related factor 2 (Nrf2);   

DOI  :  10.1186/s12974-019-1495-3

来源: publisher

【 摘 要 】

BackgroundType 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.MethodsT2DM (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-IL1β) 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.ResultsHDAC3 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-IL1β 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.ConclusionsOur experimental results show that HDAC3 might be a new therapeutic target for BBB damage in T2DM.

【 授权许可】

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