Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage.
Interest in histone deacetylase (HDAC)-based therapeutics as a potential treatment for stroke has grown dramatically. The neuroprotection of HDAC inhibition may involve multiple mechanisms, including modulation of transcription factor acetylation independent of histones. The transcription factor Nrf2 has been shown to be protective in stroke as a key regulator of antioxidant-responsive genes. Here, we hypothesized that HDAC inhibition might provide neuroprotection against mouse cerebral ischemia by activating the Nrf2 pathway. We determined that the classic HDAC inhibitor trichostatin A increased neuronal cell viability after oxygen-glucose deprivation (from an OD value of 0.10±0.01 to 0.25±0.08) and reduced infarct volume in wild-type mice with stroke (from 49.1±3.8 to 21.3±4.6%). In vitro studies showed that HDAC inhibition reduced Nrf2 suppressor Keap1 expression, induced Keap1/Nrf2 dissociation, Nrf2 nuclear translocation, and Nrf2 binding to antioxidant response elements in heme oxygenase 1 (HO1), and caused HO1 transcription. Furthermore, we demonstrated that HDAC inhibition upregulated proteins downstream of Nrf2, including HO1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit in neuron cultures and brain tissue. Finally, unlike wild-type mice, Nrf2-deficient mice were not protected by pharmacologic inhibition of HDAC after cerebral ischemia. Our studies suggest that activation of Nrf2 might be an important mechanism by which HDAC inhibition provides neuroprotection.
Nanjing University Medical School, Jiangsu Key Laboratory of Molecular Medicine, Nanjing, People's Republic of China.
Bing
B
Wang
Xiaolei
X
Zhu
YunTai
Y
Kim
Jie
J
Li
Siyuan
S
Huang
Sofiyan
S
Saleem
Rung-chi
RC
Li
Yun
Y
Xu
Sylvain
S
Dore
Wangsen
W
Cao
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000072019:Kelch-Like ECH-Associated Protein 1; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D020218:Response Elements
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; C012589:trichostatin A; D008156:Luciferases