Abstract
Histone deacetylases (HDACs) and their inhibitors affect the integrity of blood–brain barrier (BBB) which plays an important role in pathological conditions of the central nervous system (CNS). In this study, expression of HDACs was examined in bEnd.3 endothelial cells subjected to oxygen and glucose deprivation (OGD)–reperfusion injury. Expression of histone deacetylase-related protein (HDRP) produced by alternative splicing of HDAC9 was found to increase significantly in bEnd.3 cells upon OGD–reperfusion injury. HDRP was primarily localized in the nucleus. To investigate potential target genes of HDRP, its transcript was depleted by RNA interference and gene expression was determined. We found that FAS and GADD45a gene expression was up-regulated in HDRP-depleted bEnd.3 cells subjected to OGD–reperfusion injury. Interestingly, these genes are known to be involved in apoptosis and permeability of vascular endothelial cells. Our study suggests that HDRP may play a significant role in BBB integrity after CNS damage.
Similar content being viewed by others
References
Bardai FH, Price V, Zaayman M, Wang L, D’Mello SR (2012) Histone deacetylase-1 (HDAC1) is a molecular switch between neuronal survival and death. J Biol Chem 287:35444–35453
Chen J, Somanath PR, Razorenova O, Chen WS, Hay N, Bornstein P, Byzova TV (2005) Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med 11:1188–1196
Dash PK, Orsi SA, Zhang M, Grill RJ, Pati S, Zhao J, Moore AN (2010) Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PLoS One 5:e11383
Förster C, Burek M, Romero IA, Weksler B, Couraud PO, Drenckhahn D (2008) Differential effects of hydrocortisone and TNFalpha on tight junction proteins in an in vitro model of the human blood–brain barrier. J Physiol 586:1937–1949
Gloire G, Charlier E, Piette J (2008) Regulation of CD95/APO-1/Fas-induced apoptosis by protein phosphatases. Biochem Pharmacol 76:1451–1458
Green MR, Sambrook J (2012) Molecular Cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, New York
Guo G, Bhat NR (2007) p38alpha MAP kinase mediates hypoxia-induced motor neuron cell death: a potential target of minocycline’s neuroprotective action. Neurochem Res 32:2160–2166
Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185
Lavrik IN, Krammer PH (2012) Regulation of CD95/Fas signaling at the DISC. Cell Death Differ 19:36–41
Lee JY, Kim HS, Choi HY, Oh TH, Ju BG, Yune TY (2012a) Valproic acid attenuates blood–spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury. J Neurochem 121:818–829
Lee K, Na W, Lee JY, Na J, Cho H, Wu H, Yune TY, Kim WS, Ju BG (2012b) Molecular mechanism of Jmjd3-mediated interleukin-6 gene regulation in endothelial cells underlying spinal cord injury. J Neurochem 122:272–282
Morrison BE, D’Mello SR (2008) Polydactyly in mice lacking HDAC9/HDRP. Exp Biol Med 233:980–988
Morrison BE, Majdzadeh N, Zhang X, Lyles A, Bassel-Duby R, Olson EN, D’Mello SR (2006) Neuroprotection by histone deacetylase-related protein. Mol Cell Biol 26:3550–3564
Nohda K, Nakatsuka T, Takeda D, Miyazaki N, Nishi H, Sonobe H, Yoshida M (2007) Selective vulnerability to ischemia in the rat spinal cord: a comparison between ventral and dorsal horn neurons. Spine 32:1060–1066
Ogata T, Nakamura Y, Tsuji K, Okumura H, Kataoka K, Shibata T (1996) Role of aspartate in ischemic spinal cord damage. J Orthop Res 14:504–510
Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, Zelent A (2003) The histone deacetylase 9 gene encodes multiple protein isoforms. J Biol Chem 278:16059–16072
Redzic Z (2011) Molecular biology of the blood–brain and the blood–cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8:3
Simard JM, Tsymbalyuk O, Ivanov A, Ivanova S, Bhatta S, Geng Z, Woo SK, Gerzanich V (2007) Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate prOGDessive hemorrhagic necrosis following spinal cord injury. J Clin Invest 117:2105–2113
Sparrow DB, Miska EA, Langley E, Reynaud-Deonauth S, Kotecha S, Towers N, Spohr G, Kouzarides T, Mohun TJ (1999) MEF-2 function is modified by a novel co-repressor, MITR. EMBO J 18:5085–5098
Stamatovic SM, Keep RF, Andjelkovic AV (2008) Brain endothelial cell–cell junctions: how to “open” the blood brain barrier. Curr Neuropharmacol 6:179–192
Wang L, Zhou C, Wang Z, Liu J, Jing Z, Zhang Z, Wang Y (2011a) Dynamic variation of genes profiles and pathways in the hippocampus of ischemic mice: a genomic study. Brain Res 1372:13–21
Wang Z, Leng Y, Tsai LK, Leeds P, Chuang DM (2011b) Valproic acid attenuates blood–brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition. J Cereb Blood Flow Metab 31:52–57
Wang Z, Tsai LK, Munasinghe J, Leng Y, Fessler EB, Chibane F, Leeds P, Chuang DM (2012) Chronic valproate treatment enhances postischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke. Stroke 43:2430–2436
Wosik K, Biernacki K, Khouzam MP, Prat A (2007) Death receptor expression and function at the human blood brain barrier. J Neurol Sci 259:53–60
Yang XJ, Seto E (2007) HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26:5310–5318
Yang XJ, Seto E (2008) The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9:206–218
Yourick DL, Koenig ML, Durden AV, Long JB (2003) N-acetylaspartylglutamate and beta-NAAG protect against injury induced by NMDA and hypoxia in primary spinal cord cultures. Brain Res 991:56–64
Zhang CL, McKinsey TA, Olson EN (2001) The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc Natl Acad Sci USA 98:7354–7359
Zhang X, Chen HM, Jaramillo E, Wang L, D’Mello SR (2008) Histone deacetylase-related protein inhibits AES-mediated neuronal cell death by direct interaction. J Neurosci Res 86:2423–2431
Zhou X, Richon VM, Rifkind RA, Marks PA (2000) Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. Proc Natl Acad Sci USA 97:1056–1061
Acknowledgments
We thank to Dr. Tai Young Yune in Kyunghee University for valuable discussion. We also thanks to other member of the laboratory for the technical helps.
Conflict of interest
The authors have declared that no conflict of interest exists.
Author information
Authors and Affiliations
Corresponding author
Additional information
Young Ae Lee and Wonho Na are co-first authors.
Rights and permissions
About this article
Cite this article
Lee, Y.A., Na, W., Lee, K. et al. Characterization of HDAC9 isoforms in brain microvessel bEnd.3 cells upon oxygen and glucose deprivation–reperfusion injury. Genes Genom 37, 537–543 (2015). https://doi.org/10.1007/s13258-015-0282-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13258-015-0282-5