Expression patterns of histone deacetylases in experimental stroke and potential targets for neuroprotection.
1. Histone deacetylase (HDAC) inhibitors exert neuroprotection in both cellular and animal models of ischaemic stroke. However, which HDAC isoform (or isoforms) mediates this beneficial effect has not yet been determined. 2. In the present study, gene levels of the HDAC isoforms were determined in the mouse cortex using reverse transcription-polymerase chain reaction (RT-PCR), whereas changes in the expression of individual zinc-dependent HDAC family members were evaluated by western blotting, 3, 12, 24 and 48 h after cerebral ischaemia induced by transient middle cerebral artery occlusion in male Kunming mice. 3. The HDAC isoforms HDAC1-11 were all expressed in the mouse cortex and differentially affected by cerebral ischaemia. Notably, there was a substantial increase in HDAC3, HDAC6 and HDAC11 expression during the early phases of experimental stroke, indicating their contribution to stroke pathogenesis. Furthermore, induction of HDAC3 and HDAC6 in cortical neurons by ischaemic stroke was confirmed in vivo and in vitro using double-labelled immunostaining and RT-PCR, respectively. Therefore, small hairpin (sh) RNAs were used to selectively knock down HDAC3 or HDAC6. This knockdown appreciably promoted the survival of cortical neurons subjected to oxygen and glucose deprivation. 4. The findings of the present study demonstrate the expression patterns of HDAC isoforms during experimental ischaemic stroke. Furthermore, HDAC3 and HDAC6 were identified as potential mediators in the neurotoxicity of ischaemic stroke, suggesting that specific therapeutic approaches may be considered according to HDAC subtype.
Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Yan-Ting
YT
Chen
Xue-Feng
XF
Zang
Jie
J
Pan
Xiao-Lei
XL
Zhu
Fei
F
Chen
Zhi-Bin
ZB
Chen
Yun
Y
Xu
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000099186:Histone Deacetylase 3
D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D000099186:Histone Deacetylase 3; C499033:Hdac6 protein, mouse