title: 17β-estradiol increases expression of the oxidative stress response and DNA repair protein apurinic endonuclease (Ape1) in the cerebral cortex of female mice following hypoxia.
abstract: While it is well established that 17β-estradiol (E2) protects the rodent brain from ischemia-induced damage, it has been unclear how this neuroprotective effect is mediated. Interestingly, convincing evidence has also demonstrated that maintaining or increasing the expression of the oxidative stress response and DNA repair protein apurinic endonuclease 1 (Ape1) is instrumental in reducing ischemia-induced damage in the brain. Since E2 increases expression of the oxidative stress response proteins Cu/Zn superoxide dismutase and thioredoxin in the brain, we hypothesized that E2 may also increase Ape1 expression and that this E2-induced expression of Ape1 may help to mediate the neuroprotective effects of E2 in the brain. To test this hypothesis, we utilized three model systems including primary cortical neurons, brain slice cultures, and whole animals. Although estrogen receptor α and Ape1 were expressed in primary cortical neurons, E2 did not alter Ape1 expression in these cells. However, immunofluorescent staining and quantitative Western blot analysis demonstrated that estrogen receptor α and Ape1 were expressed in the nuclei of cortical neurons in brain slice cultures and that E2 increased Ape1 expression in the cerebral cortex of these cultures. Furthermore, Ape1 expression was increased and oxidative DNA damage was decreased in the cerebral cortices of ovariectomized female C57Bl/6J mice that had been treated with E2 and exposed to hypoxia. Taken together, our studies demonstrate that the neuronal microenvironment may be required for increased Ape1 expression and that E2 enhances expression of Ape1 and reduces oxidative DNA damage, which may in turn help to reduce ischemia-induced damage in the cerebral cortex and mediate the neuroprotective effects of E2.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Dietrich
authors.forename: Gwendolyn I
authors.initials: GI
authors.lastname: Humphreys
authors.forename: Ann M
authors.initials: AM
authors.lastname: Nardulli
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D000860:Hypoxia; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D004958:Estradiol; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: 17β-estradiol; 4′,6-diamidino-2-phenylindole; 8-OHG; 8-hydroxydeoxyguanosine; Ape1; Apurinic endonuclease 1; DAPI; E(2); ERα; ERβ; Estrogen; Estrogen receptor; Hypoxia; Neuroprotection; ROS; RPL7; Reactive oxygen species; apurinic endonuclease 1; estrogen receptor α; estrogen receptor β; reactive oxygen species; ribosomal protein L7
references.citation: BMJ. 1988 Aug 20-27;297(6647):519-22
references.pmid: 3139181
references.citation: Front Neuroendocrinol. 2009 Jul;30(2):201-11
references.pmid: 19401209
references.citation: Sci Aging Knowledge Environ. 2001 Oct 03;2001(1):oa5
references.pmid: 14602949
references.citation: Climacteric. 2012 Jun;15(3):217-28
references.pmid: 22612607
references.citation: Cancer Res. 1994 Jan 1;54(1):12-5
references.pmid: 8261431
references.citation: J Neurocytol. 2000 May-Jun;29(5-6):401-10
references.pmid: 11424956
references.citation: Mutat Res. 2000 Oct 16;461(2):83-108
references.pmid: 11018583
references.citation: Cerebrovasc Dis. 2006;21 Suppl 2:48-53
references.pmid: 16651814
references.citation: J Neurosci. 1999 Aug 1;19(15):6385-93
references.pmid: 10414967
references.citation: J Cereb Blood Flow Metab. 2010 May;30(5):935-42
references.pmid: 20010956
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4131-6
references.pmid: 10097175
references.citation: Mol Endocrinol. 1995 Nov;9(11):1441-54
references.pmid: 8584021
references.citation: Biol Reprod. 1981 May;24(4):820-30
references.pmid: 7018601
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20265-70
references.pmid: 22114196
references.citation: Dev Cell. 2004 Aug;7(2):205-16
references.pmid: 15296717
references.citation: Endocrinology. 1992 Feb;130(2):805-10
references.pmid: 1733727
references.citation: BMC Genomics. 2011 Oct 11;12:499
references.pmid: 21988864
references.citation: Antioxid Redox Signal. 2004 Feb;6(1):81-7
references.pmid: 14713338
references.citation: J Cereb Blood Flow Metab. 2003 Nov;23(11):1324-39
references.pmid: 14600440
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3204-9
references.pmid: 20133634
references.citation: Mol Cell Neurosci. 2010 Nov;45(3):267-76
references.pmid: 20637286
references.citation: J Mol Endocrinol. 2009 Dec;43(6):251-61
references.pmid: 19620238
references.citation: Prog Neurobiol. 2001 Jan;63(1):29-60
references.pmid: 11040417
references.citation: J Cereb Blood Flow Metab. 1998 Nov;18(11):1253-8
references.pmid: 9809515
references.citation: FASEB J. 2003 May;17(8):947-8
references.pmid: 12626428
references.citation: J Cereb Blood Flow Metab. 1999 May;19(5):495-501
references.pmid: 10326716
references.citation: FASEB J. 2003 Aug;17(11):1541-3
references.pmid: 12824304
references.citation: J Biol Chem. 2000 Feb 18;275(7):4618-27
references.pmid: 10671489
references.citation: EMBO J. 1992 Feb;11(2):653-65
references.pmid: 1537340
references.citation: Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11158-62
references.pmid: 1763030
references.citation: Circulation. 1987 Jun;75(6):1102-9
references.pmid: 3568321
references.citation: BMC Neurosci. 2006 Mar 13;7:24
references.pmid: 16533397
references.citation: J Steroid Biochem Mol Biol. 2011 Nov;127(3-5):382-9
references.pmid: 21704159
references.citation: JAMA. 2007 Apr 4;297(13):1465-77
references.pmid: 17405972
references.citation: J Neurosci Methods. 1991 Apr;37(2):173-82
references.pmid: 1715499
references.citation: Cell Res. 2008 Jan;18(1):27-47
references.pmid: 18166975
references.citation: Endocrine. 2003 Jun;21(1):11-5
references.pmid: 12777698
references.citation: Eur J Neurosci. 2003 Jul;18(1):85-94
references.pmid: 12859340
references.citation: Cell. 1991 Aug 23;66(4):685-96
references.pmid: 1652370
references.citation: Maturitas. 1990 Sep;12(3):259-85
references.pmid: 2145495
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3633-8
references.pmid: 9108029
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1952-7
references.pmid: 11172057
references.citation: Neuroscience. 2006 Sep 15;141(4):1721-30
references.pmid: 16777351
references.citation: Glia. 2010 Jan 1;58(1):93-102
references.pmid: 19533603
references.citation: Nat Struct Biol. 2000 Mar;7(3):176-8
references.pmid: 10700268
references.citation: J Biol Chem. 1994 Dec 9;269(49):31234-42
references.pmid: 7983067
references.citation: Annu Rev Biochem. 1988;57:29-67
references.pmid: 3052275
references.citation: Stroke. 2000 Jan;31(1):155-60
references.pmid: 10625732
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4130-5
references.pmid: 15024130
references.citation: Psychoneuroendocrinology. 1999 Aug;24(6):657-77
references.pmid: 10399774
references.citation: Stroke. 1999 Nov;30(11):2408-15
references.pmid: 10548678
references.citation: Neurosurgery. 1998 Dec;43(6):1382-96; discussion 1396-7
references.pmid: 9848853
references.citation: Science. 2006 Jun 30;312(5782):1882-3
references.pmid: 16809515
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8919-23
references.pmid: 8799128
references.citation: J Neurosci. 2003 Dec 10;23(36):11420-6
references.pmid: 14673006
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6013-8
references.pmid: 17389368
references.citation: Mol Cell Biol. 1995 Oct;15(10):5363-8
references.pmid: 7565686
references.citation: Mutat Res. 2007 Jan 3;614(1-2):24-36
references.pmid: 16879837
references.citation: Genes Dev. 1997 Mar 1;11(5):558-70
references.pmid: 9119221
references.citation: J Neurosci. 2000 Jul 15;20(14):5329-38
references.pmid: 10884317
references.citation: Biochim Biophys Acta. 2010 Oct;1800(10):1106-12
references.pmid: 19818384
references.citation: Nucleic Acids Res. 2001 Mar 15;29(6):1285-92
references.pmid: 11238994
references.citation: Exp Biol Med (Maywood). 2006 May;231(5):514-21
references.pmid: 16636299
references.citation: J Comp Neurol. 2007 Feb 20;500(6):1064-75
references.pmid: 17183542
references.citation: J Cereb Blood Flow Metab. 2001 Jan;21(1):2-14
references.pmid: 11149664
references.citation: Drug Discov Today. 2005 Jul 15;10(14):993-1000
references.pmid: 16023058
references.citation: Stroke. 1999 Feb;30(2):441-8; discussion 449
references.pmid: 9933285
references.citation: Brain. 2002 Nov;125(Pt 11):2549-57
references.pmid: 12390979
references.citation: DNA Repair (Amst). 2007 Mar 1;6(3):317-28
references.pmid: 17126083
references.citation: EMBO J. 2012 May 30;31(11):2448-60
references.pmid: 22562152
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2842-7
references.pmid: 12604781
references.citation: Prev Med. 1991 Jan;20(1):47-63
references.pmid: 1826173
references.citation: Am J Pathol. 2000 Mar;156(3):965-76
references.pmid: 10702412
references.citation: Brain Res Brain Res Rev. 2001 Nov;37(1-3):313-9
references.pmid: 11744096
references.citation: Mol Endocrinol. 2008 May;22(5):1113-24
references.pmid: 18258688
references.citation: J Biol Chem. 2002 Nov 15;277(46):44548-56
references.pmid: 12213807
references.citation: Endocrinology. 2006 Jun;147(6):3076-84
references.pmid: 16527848
references.citation: Endocrinology. 2010 Oct;151(10):4916-25
references.pmid: 20685874
references.citation: J Vis Exp. 2007;(10):562
references.pmid: 18989405
references.citation: Brain Res. 2009 Jun 5;1274:1-10
references.pmid: 19374886
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12365-70
references.pmid: 17640893
references.citation: Brain Res. 2004 Jun 4;1010(1-2):22-34
references.pmid: 15126114
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9614-9
references.pmid: 12878732
references.citation: Neuroreport. 1998 Dec 21;9(18):4015-8
references.pmid: 9926839
references.citation: J Neurosci. 2003 Jan 15;23(2):384-91
references.pmid: 12533598
references.citation: Arteriosclerosis. 1990 Nov-Dec;10(6):1051-7
references.pmid: 2244855
references.citation: J Neurochem. 2005 Apr;93(2):351-8
references.pmid: 15816858
references.citation: Nucleic Acids Res. 2001 Jan 15;29(2):430-8
references.pmid: 11139613
references.citation: Mutat Res. 2001 Jun 5;486(1):31-40
references.pmid: 11356334
references.citation: Steroids. 2007 May;72(5):381-405
references.pmid: 17379265
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5739-43
references.pmid: 15824325
references.citation: J Cereb Blood Flow Metab. 2006 Feb;26(2):181-98
references.pmid: 16001017