Deletion of mitochondrial uncoupling protein-2 increases ischemic brain damage after transient focal ischemia by altering gene expression patterns and enhancing inflammatory cytokines.
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.
Haines
Bryan A
BA
Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada, USA.
Mehta
Suresh L
SL
Pratt
Serena M
SM
Warden
Craig H
CH
Li
P Andy
PA
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
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
Brain Res. 1998 Aug 31;804(1):36-44
9729262
J Cereb Blood Flow Metab. 2002 Mar;22(3):308-17
11891436
Biochem J. 2002 Aug 15;366(Pt 1):45-55
12020353
Neuroscience. 1998 Jun;84(4):1097-112
9578398
J Neurosci Res. 1998 Aug 1;53(3):279-96
9698156
J Neurochem. 2004 Jun;89(5):1283-92
15147521
Neuropathology. 2007 Oct;27(5):442-7
18018477
Neuroreport. 1993 Dec 13;5(3):293-6
8298091
Neuroscience. 2009 Feb 6;158(3):995-1006
18675321
Nat Med. 2003 Aug;9(8):1062-8
12858170
J Cereb Blood Flow Metab. 2001 Jun;21(6):683-9
11488537
Exp Neurol. 2005 Jun;193(2):350-60
15869937
J Transl Med. 2009 Nov 17;7:97
19919699
Biochem Pharmacol. 2002 Aug 1;64(3):363-7
12147286
Endocrinology. 2004 May;145(5):2412-20
14749353
Neuroscience. 2009 Mar 31;159(3):993-1002
19356683
J Cereb Blood Flow Metab. 2008 Oct;28(10):1707-21
18575457
Neuroscience. 2010 Feb 3;165(3):705-14
19909792
Mult Scler. 2009 Nov;15(11):1271-9
19805441
Nat Genet. 2000 Dec;26(4):435-9
11101840
J Neurosci. 2003 Mar 1;23(5):1710-8
12629175
J Cereb Blood Flow Metab. 2009 Jun;29(6):1069-78
19240738
J Pharmacol Sci. 2006;100(5):461-70
16682788
Curr Neurovasc Res. 2009 Nov;6(4):213-22
19807658
J Immunol. 1998 Jan 15;160(2):970-8
9551936
Int J Biochem Cell Biol. 2002 Oct;34(10):1190-206
12127570
J Cereb Blood Flow Metab. 1998 Feb;18(2):196-205
9469163
Cancer Res. 1998 Apr 15;58(8):1670-6
9563481
Circ Res. 2003 Aug 8;93(3):192-200
12855674
J Cereb Blood Flow Metab. 2006 May;26(5):654-65
16121126
J Biol Chem. 2005 May 13;280(19):19062-9
15757894
Endocrinology. 2009 Jul;150(7):3040-8
19246534
Eur J Cancer. 2002 Oct;38(15):2058-65
12376212
J Cereb Blood Flow Metab. 2003 Jun;23(6):748-55
12796723
Brain Res. 2003 Dec 12;993(1-2):140-5
14642839
J Cereb Blood Flow Metab. 2008 Jun;28(6):1186-95
18301432
Eur J Neurosci. 2002 May;15(10):1663-8
12059974
Stroke. 1996 Jun;27(6):1124-9
8650725
Cancer Cell. 2003 Oct;4(4):321-8
14585359
Clin Chem Lab Med. 1999 Mar;37(3):205-8
10353462
Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S46-8
17462780
Cell Stress Chaperones. 2006 Summer;11(2):180-6
16817324