title: Deletion of mitochondrial uncoupling protein-2 increases ischemic brain damage after transient focal ischemia by altering gene expression patterns and enhancing inflammatory cytokines.
abstract: Mitochondrial hyperpolarization inhibits the electron transport chain and increases incomplete reduction of oxygen, enabling production of reactive oxygen species (ROS). The consequence is mitochondrial damage that eventually causes cell death. Uncoupling proteins (UCPs) are inner mitochondrial membrane proteins that dissipate the mitochondrial proton gradient by transporting H(+) across the inner membrane, thereby stabilizing the inner mitochondrial membrane potential and reducing the formation of ROS. The role of UCP2 in neuroprotection is still in debate. This study seeks to clarify the role of UCP2 in transient focal ischemia (tFI) and to further understand the mechanisms of ischemic brain damage. Both wild-type and UCP2-knockout mice were subjected to tFI. Knocking out UCP2 significantly increased the infarct volume to 61% per hemisphere as compared with 18% in wild-type animals. Knocking out UCP2 suppressed antioxidant, cell-cycle, and DNA repair genes, including Sod1 and Sod2, Gstm1, and cyclins. Furthermore, knocking out UCP2 significantly upregulated the protein levels of the inflammatory cytokines, including CTACK, CXCL16, Eotaxin-2, fractalkine, and BLC. It is concluded that knocking out the UCP2 gene exacerbates neuronal death after cerebral ischemia with reperfusion and this detrimental effect is mediated by alteration of antioxidant genes and upregulation of inflammatory mediators.
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada, USA.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Haines
authors.forename: Suresh L
authors.initials: SL
authors.lastname: Mehta
authors.forename: Serena M
authors.initials: SM
authors.lastname: Pratt
authors.forename: Craig H
authors.initials: CH
authors.lastname: Warden
authors.forename: P Andy
authors.initials: PA
authors.lastname: Li
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology; D002560:Cerebrovascular Circulation; D054428:Chemokine CX3CL1 / Q000378:metabolism; D003199:Computer Systems; D016207:Cytokines / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D000071246:Uncoupling Protein 2
chemical_list: D054428:Chemokine CX3CL1; D016207:Cytokines; D018836:Inflammation Mediators; D007473:Ion Channels; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2
references.citation: Brain Res. 1998 Aug 31;804(1):36-44
references.pmid: 9729262
references.citation: J Cereb Blood Flow Metab. 2002 Mar;22(3):308-17
references.pmid: 11891436
references.citation: Biochem J. 2002 Aug 15;366(Pt 1):45-55
references.pmid: 12020353
references.citation: Neuroscience. 1998 Jun;84(4):1097-112
references.pmid: 9578398
references.citation: J Neurosci Res. 1998 Aug 1;53(3):279-96
references.pmid: 9698156
references.citation: J Neurochem. 2004 Jun;89(5):1283-92
references.pmid: 15147521
references.citation: Neuropathology. 2007 Oct;27(5):442-7
references.pmid: 18018477
references.citation: Neuroreport. 1993 Dec 13;5(3):293-6
references.pmid: 8298091
references.citation: Neuroscience. 2009 Feb 6;158(3):995-1006
references.pmid: 18675321
references.citation: Nat Med. 2003 Aug;9(8):1062-8
references.pmid: 12858170
references.citation: J Cereb Blood Flow Metab. 2001 Jun;21(6):683-9
references.pmid: 11488537
references.citation: Exp Neurol. 2005 Jun;193(2):350-60
references.pmid: 15869937
references.citation: J Transl Med. 2009 Nov 17;7:97
references.pmid: 19919699
references.citation: Biochem Pharmacol. 2002 Aug 1;64(3):363-7
references.pmid: 12147286
references.citation: Endocrinology. 2004 May;145(5):2412-20
references.pmid: 14749353
references.citation: Neuroscience. 2009 Mar 31;159(3):993-1002
references.pmid: 19356683
references.citation: J Cereb Blood Flow Metab. 2008 Oct;28(10):1707-21
references.pmid: 18575457
references.citation: Neuroscience. 2010 Feb 3;165(3):705-14
references.pmid: 19909792
references.citation: Mult Scler. 2009 Nov;15(11):1271-9
references.pmid: 19805441
references.citation: Nat Genet. 2000 Dec;26(4):435-9
references.pmid: 11101840
references.citation: J Neurosci. 2003 Mar 1;23(5):1710-8
references.pmid: 12629175
references.citation: J Cereb Blood Flow Metab. 2009 Jun;29(6):1069-78
references.pmid: 19240738
references.citation: J Pharmacol Sci. 2006;100(5):461-70
references.pmid: 16682788
references.citation: Curr Neurovasc Res. 2009 Nov;6(4):213-22
references.pmid: 19807658
references.citation: J Immunol. 1998 Jan 15;160(2):970-8
references.pmid: 9551936
references.citation: Int J Biochem Cell Biol. 2002 Oct;34(10):1190-206
references.pmid: 12127570
references.citation: J Cereb Blood Flow Metab. 1998 Feb;18(2):196-205
references.pmid: 9469163
references.citation: Cancer Res. 1998 Apr 15;58(8):1670-6
references.pmid: 9563481
references.citation: Circ Res. 2003 Aug 8;93(3):192-200
references.pmid: 12855674
references.citation: J Cereb Blood Flow Metab. 2006 May;26(5):654-65
references.pmid: 16121126
references.citation: J Biol Chem. 2005 May 13;280(19):19062-9
references.pmid: 15757894
references.citation: Endocrinology. 2009 Jul;150(7):3040-8
references.pmid: 19246534
references.citation: Eur J Cancer. 2002 Oct;38(15):2058-65
references.pmid: 12376212
references.citation: J Cereb Blood Flow Metab. 2003 Jun;23(6):748-55
references.pmid: 12796723
references.citation: Brain Res. 2003 Dec 12;993(1-2):140-5
references.pmid: 14642839
references.citation: J Cereb Blood Flow Metab. 2008 Jun;28(6):1186-95
references.pmid: 18301432
references.citation: Eur J Neurosci. 2002 May;15(10):1663-8
references.pmid: 12059974
references.citation: Stroke. 1996 Jun;27(6):1124-9
references.pmid: 8650725
references.citation: Cancer Cell. 2003 Oct;4(4):321-8
references.pmid: 14585359
references.citation: Clin Chem Lab Med. 1999 Mar;37(3):205-8
references.pmid: 10353462
references.citation: Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S46-8
references.pmid: 17462780
references.citation: Cell Stress Chaperones. 2006 Summer;11(2):180-6
references.pmid: 16817324