Abstract
Nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4), a transcriptional factor, is involved in the control about the flow of genetic information and the modulation of diverse cellular activities. Accumulating evidence has demonstrated that NFATc4 exerted a pro-apoptotic effect in multiple diseases. Here, we explored the NFATc4’s roles during the pathophysiological processes of intracerebral hemorrhage (ICH). An ICH rat model was built and evaluated according to behavioral testing. Using Western blot, immunohistochemistry, and immunofluorescence, significant up-regulation of NFATc4 was found in neurons in brain areas surrounding the hematoma following ICH. Increasing NFATc4 expression was found to be accompanied by the up-regulation of Fas ligand (FasL), active caspase-8, and active caspase-3, respectively. Besides, NFATc4 co-localized with active caspase-3 in neurons, indicating its role in neuronal apoptosis. Our in vitro study, using NFATc4 RNA interference in PC12 cells, further confirmed that NFATc4 might exert its pro-apoptotic function in neuronal apoptosis through extrinsic pathway. Thus, NFATc4 may play a role in promoting the brain secondary damage following ICH.
Similar content being viewed by others
References
Albeck JG, Burke JM, Aldridge BB, Zhang M, Lauffenburger DA, Sorger PK (2008) Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol Cell 30:11–25
Aronowski J, Zhao X (2011) Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 42:1781–1786
Bradl M, Lassmann H (2010) Oligodendrocytes: biology and pathology. Acta Neuropathol 119:37–53
Bradley KC, Groth RD, Mermelstein PG (2005) Immunolocalization of NFATc4 in the adult mouse brain. J Neurosci Res 82:762–770
Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443:796–802
Bushdid PB, Osinska H, Waclaw RR, Molkentin JD, Yutzey KE (2003) NFATc3 and NFATc4 are required for cardiac development and mitochondrial function. Circ Res 92:1305–1313
Chandrasekar B, Patel DN, Mummidi S, Kim JW, Clark RA, Valente AJ (2008) Interleukin-18 suppresses adiponectin expression in 3T3-L1 adipocytes via a novel signal transduction pathway involving ERK1/2-dependent NFATc4 phosphorylation. J Biol Chem 283:4200–4209
Crandall KM, Rost NS, Sheth KN (2011) Prognosis in intracerebral hemorrhage. Rev Neurol Dis 8:23–29
Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516
Gomez-Sintes R, Lucas JJ (2010) NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy. J Clin Invest 120:2432–2445
Groth RD, Mermelstein PG (2003) Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci 23:8125–8134
Han Z, Hendrickson EA, Bremner TA, Wyche JH (1997) A sequential two-step mechanism for the production of the mature p17:p12 form of caspase-3 in vitro. J Biol Chem 272:13432–13436
Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G (2002) Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33:2478–2484
Ikram MA, Wieberdink RG, Koudstaal PJ (2012) International epidemiology of intracerebral hemorrhage. Curr Atheroscler Rep 14:300–306
Jayanthi S, Deng X, Ladenheim B, McCoy MT, Cluster A, Cai NS, Cadet JL (2005) Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis. Proc Natl Acad Sci USA 102:868–873
Karabiyikoglu M, Hua Y, Keep RF, Ennis SR, Xi G (2004) Intracerebral hirudin injection attenuates ischemic damage and neurologic deficits without altering local cerebral blood flow. J Cereb Blood Flow Metab 24:159–166
Luoma JI, Zirpel L (2008) Deafferentation-induced activation of NFAT (nuclear factor of activated T-cells) in cochlear nucleus neurons during a developmental critical period: a role for NFATc4-dependent apoptosis in the CNS. J Neurosci 28:3159–3169
Matsushita K, Meng W, Wang X, Asahi M, Asahi K, Moskowitz MA, Lo EH (2000) Evidence for apoptosis after intercerebral hemorrhage in rat striatum. J Cereb Blood Flow Metab 20:396–404
Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104
Putcha GV, Harris CA, Moulder KL, Easton RM, Thompson CB, Johnson EM Jr (2002) Intrinsic and extrinsic pathway signaling during neuronal apoptosis: lessons from the analysis of mutant mice. J Cell Biol 157:441–453
Quadrato G, Benevento M, Alber S, Jacob C, Floriddia EM, Nguyen T, Elnaggar MY, Pedroarena CM, Molkentin JD, Di Giovanni S (2012) Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus. Proc Natl Acad Sci USA 109:E1499–E1508
Qureshi AI, Suri MF, Ostrow PT, Kim SH, Ali Z, Shatla AA, Guterman LR, Hopkins LN (2003) Apoptosis as a form of cell death in intracerebral hemorrhage. Neurosurgery 52:1041–1047 discussion 1047–1048
Sattler R, Tymianski M (2001) Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol 24:107–129
Schneider P, Tschopp J (2000) Apoptosis induced by death receptors. Pharm Acta Helv 74:281–286
Stoica BA, Byrnes KR, Faden AI (2009) Cell cycle activation and CNS injury. Neurotox Res 16:221–237
Viswanathan A, Greenberg SM (2009) Intracerebral hemorrhage. Handb Clin Neurol 93:767–790
Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27:894–908
Williams RW, Rakic P (1988) Three-dimensional counting: an accurate and direct method to estimate numbers of cells in sectioned material. J Comp Neurol 278:344–352
Wu H, Peisley A, Graef IA, Crabtree GR (2007) NFAT signaling and the invention of vertebrates. Trends Cell Biol 17:251–260
Wu J, Yang S, Xi G, Song S, Fu G, Keep RF, Hua Y (2008) Microglial activation and brain injury after intracerebral hemorrhage. Acta Neurochir Suppl 105:59–65
Xue M, Del Bigio MR (2000) Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neurosci Lett 283:230–232
Yang S, Song S, Hua Y, Nakamura T, Keep RF, Xi G (2008) Effects of thrombin on neurogenesis after intracerebral hemorrhage. Stroke 39:2079–2084
Conflict of interest
We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.
Author information
Authors and Affiliations
Corresponding author
Additional information
Lei Li and Kaifu Ke contributed equally to this work.
Rights and permissions
About this article
Cite this article
Li, L., Ke, K., Tan, X. et al. Up-regulation of NFATc4 Involves in Neuronal Apoptosis Following Intracerebral Hemorrhage. Cell Mol Neurobiol 33, 893–905 (2013). https://doi.org/10.1007/s10571-013-9955-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-013-9955-2