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CaMKII Activates ASK1 to Induce Apoptosis of Spinal Astrocytes Under Oxygen–Glucose Deprivation

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Abstract

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous, structurally complex multifunctional protein serine/threonine kinase that plays an important role in cell apoptosis via linking the ER stress and mitochondrial apoptosis pathways. Recently, CaMKII has been correlated with apoptosis signal-regulating kinase 1 (ASK1) activity and the ASK1-dependent apoptosis pathway through the direct phosphorylation of Thr845 of ASK1. The specific role of CaMKII in hypoxia–reoxygenation (H/R)-induced spinal astrocyte apoptosis, however, remains unclear. In this study, we investigated the effects of CaMKIIγ (an isoform of CaMKII) on spinal astrocyte apoptosis using an in vitro oxygen–glucose deprivation (OGD/R) model which mimics hypoxic/ischemic conditions in vivo. OGD/R increased cell death and the activation of CaMKII. Deletion of CaMKIIγ results in the reduced activation of CaMKII and apoptosis in astrocytes under OGD/R conditions. Notably, the deletion of CaMKIIγ induced ASK1 phosphorylation at Thr845 in astrocytes. The activation of JNK and p38 and the downstream effect of ASK1 were also reduced. These data suggest that CaMKIIγ is required for the CaMKII-dependent regulation of ASK1, affecting the apoptosis of a biologically important cell type under spinal cord injury.

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References

  • Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nature Rev 7:41–53

    Article  CAS  Google Scholar 

  • Ahmad A, Genovese T, Impellizzeri D, Crupi R, Velardi E, Marino A, Esposito E, Cuzzocrea S (2012) Reduction of ischemic brain injury by administration of palmitoylethanolamide after transient middle cerebral artery occlusion in rats. Brain Res 1477:45–58

    Article  PubMed  CAS  Google Scholar 

  • Baregamian N, Song J, Bailey CE, Papaconstantinou J, Evers BM, Chung DH (2009) Tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy, and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis. Oxid Med Cell Longev 2:297–306

    Article  PubMed  Google Scholar 

  • Benavides A, Pastor D, Santos P, Tranque P, Calvo S (2005) CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose deprivation. Glia 52:261–275

    Article  PubMed  Google Scholar 

  • Benov L, Sztejnberg L, Fridovich I (1998) Critical evaluation of the use of hydroethidine as a measure of superoxide anion radical. Free Radic Biol Med 25:826–831

    Article  PubMed  CAS  Google Scholar 

  • Brnjic S, Olofsson MH, Havelka AM, Linder S (2010) Chemical biology suggests a role for calcium signaling in mediating sustained JNK activation during apoptosis. Mol Biosyst 6:764–767

    Article  Google Scholar 

  • Bruno VM, Goldberg MP, Dugan LL, Giffard RG, Choi DW (1994) Neuroprotective effect of hypothermia in cortical cultures exposed to oxygen–glucose deprivation or excitatory amino acids. J Neurochem 63:1398–1406

    Article  PubMed  CAS  Google Scholar 

  • Cabezas R, El-Bachá RS, González J, Barreto GE (2012) Mitochondrial functions in astrocytes: neuroprotective implications from oxidative damage by rotenone. Neurosci Res 13:3510–3524

    Google Scholar 

  • Gabryel B, Bielecka A, Bernacki J, Łabuzek K, Herman ZS (2011) Immunosuppressant cytoprotection correlates with HMGB1 suppression in primary astrocyte cultures exposed to combined oxygen–glucose deprivation. Pharmacol Rep 63:392–402

    PubMed  CAS  Google Scholar 

  • Guo J, Duckles SP, Weiss JH, Li X, Krause DN (2012) 17β-Estradiol prevents cell death and mitochondrial dysfunction by an estrogen receptor-dependent mechanism in astrocytes after oxygen–glucose deprivation/reperfusion. Free Radic Biol Med 52:2151–2160

    Article  PubMed  CAS  Google Scholar 

  • Jung SE, Kim YK, Youn DY, Lim MH, Ko JH, Ahn YS, Lee JH (2010) Down-modulation of Bis sensitizes cell death in C6 glioma cells induced by oxygen–glucose deprivation. Brain Res 1349:1–10

    Article  PubMed  CAS  Google Scholar 

  • Kashiwase K, Higuchi Y, Hirotani S, Yamaguchi O, Hikoso S, Takeda T, Watanabe T, Taniike M, Nakai A, Tsujimoto I, Matsumura Y, Ueno H, Nishida K, Hori M, Otsu K (2005) CaMKII activates ASK1 and NF-kappaB to induce cardiomyocyte hypertrophy. Biochem Biophys Res Commun 327:136–142

    Article  PubMed  CAS  Google Scholar 

  • Kim HS, Lee MS (2007) STAT1 as a key modulator of cell death. Cell Signal 19:454–465

    Article  PubMed  CAS  Google Scholar 

  • Kitao T, Takuma K, Kawasaki T, Inoue Y, Ikehara A, Nashida T, Ago Y, Matsuda T (2010) The Na+/Ca2+ exchanger-mediated Ca2+ influx triggers nitric oxide-induced cytotoxicity in cultured astrocytes. Neurochem Int 57:58–66

    Article  PubMed  CAS  Google Scholar 

  • Kurnellas MP, Nicot A, Shull GE, Elkabes S (2005) Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury. FASEB J 19:298–300

    PubMed  CAS  Google Scholar 

  • Manaenko A, Sun X, Kim C, Yan J, Ma Q, Zhang JH (2012) PAR-1 antagonist SCH79797 ameliorates apoptosis following surgical brain injury through inhibition of ASK1-JNK in rats Neurobiol Dis [Epub ahead of print] PMID: 23000356

  • Mayer P, Mohlig M, Idlibe D, Pfeiffer A (1995) Novel and uncommon isoforms of the calcium sensing enzyme calcium/calmodulin dependent protein kinase II in heart tissue. Basic Res Cardiol 90:372–379

    Article  PubMed  CAS  Google Scholar 

  • McDonald JW, Belegu V (2006) Demyelination and remyelination after spinal cord injury. J Neurotrauma 23:345–359

    Article  PubMed  Google Scholar 

  • Mockett BG, Gu′evremont D, Wutte M, Hulme SR, Williams JM, Abraham WC (2011) Calcium/calmodulindependent protein kinase II mediates group I metabotropic glutamate receptor-dependent protein synthesis and longterm depression in rat hippocampus. J Neurosci 31:7380–7391

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa H, Hirata Y, Takeda K, Hayakawa Y, Sato T, Kinoshita H, Sakamoto K, Nakata W, Hikiba Y, Omata M, Yoshida H, Koike K, Ichijo H, Maeda S (2011) Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase. Hepatology 54:185–195

    Article  PubMed  CAS  Google Scholar 

  • Ouyang YB, Xu LJ, Emery JF, Lee AS, Giffard RG (2011) Overexpressing GRP78 influences Ca2+ handling and function of mitochondria in astrocytes after ischemia-like stress. Mitochondrion 11:279–286

    Article  PubMed  CAS  Google Scholar 

  • Petronilli V, Miotto G, Canton M, Brini M, Colonna R, Bernardi P, Di Lisa F (1999) Transient and long-lasting openings of the mitochondrial permeability transition pore can be monitored directly in intact cells by changes in mitochondrial calcein fluorescence. Biophys J 76:725–734

    Article  PubMed  CAS  Google Scholar 

  • Shiizaki S, Naguro I, Ichijo H (2012) Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling Adv Biol Regul [Epub ahead of print] PMID: 23031789

  • Swarnkar S, Singh S, Goswami P, Mathur R, Patro IK, Nath C (2012) Astrocyte activation: a key step in rotenone induced cytotoxicity and DNA damage. Neurochem Res 37:2178–2189

    Article  PubMed  CAS  Google Scholar 

  • Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Matsuzawa A, Nishitoh H, Tobiume K, Kishida S, Ninomiya-Tsuji J, Matsumoto K, Ichijo H (2004) Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO Rep 5:161–166

    Article  PubMed  CAS  Google Scholar 

  • Timmins JM, Ozcan L, Seimon TA, Li G, Malagelada C, Backs J, Backs T, Bassel-Duby R, Olson EN, Anderson ME, Tabas I (2009) Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J Clin Invest 119:2925–2941

    Article  PubMed  CAS  Google Scholar 

  • Tohda C, Kuboyama T (2011) Current and future therapeutic strategies for functional repair of spinal cord injury. Pharmacol Ther 132:57–71

    Article  PubMed  CAS  Google Scholar 

  • Wang GH, Jiang ZL, Li YC, Li X, Shi H, Gao YQ, Vosler PS, Chen J (2011) Free-radical scavenger edaravone treatment confers neuroprotection against traumatic brain injury in rats. J Neurotrauma 28:2123–2134

    Article  PubMed  Google Scholar 

  • Zhang Y, Sun LG, Ye LP, Wang B, Li Y (2008) Lead-induced stress response in endoplasmic reticulum of astrocytes in CNS. Toxicol Mech Methods 18:751–757

    Article  PubMed  CAS  Google Scholar 

  • Zhang A, Zhang J, Sun P, Yao C, Su C, Sui T, Huang H, Cao X, Ge Y (2010) EIF2alpha and caspase-12 activation are involved in oxygen–glucose–serum deprivation/restoration-induced apoptosis of spinal cord astrocytes. Neurosci Lett 478:32–36

    Article  PubMed  CAS  Google Scholar 

  • Zhao G, Flavin MP (2000) Differential sensitivity of rat hippocampal and cortical astrocytes to oxygen–glucose deprivation injury. Neurosci Lett 285:177–180

    Article  PubMed  CAS  Google Scholar 

  • Zheng C, Han J, Xia W, Shi S, Liu J, Ying W (2012) NAD(+) administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia. Neurosci Lett 512:67–71

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Jianning Zhao.

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Liu, G., Zhao, J., Chang, Z. et al. CaMKII Activates ASK1 to Induce Apoptosis of Spinal Astrocytes Under Oxygen–Glucose Deprivation. Cell Mol Neurobiol 33, 543–549 (2013). https://doi.org/10.1007/s10571-013-9920-0

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  • DOI: https://doi.org/10.1007/s10571-013-9920-0

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