Iron regulatory protein-2 knockout increases perihematomal ferritin expression and cell viability after intracerebral hemorrhage.
Iron is deposited in perihematomal tissue after an intracerebral hemorrhage (ICH), and may contribute to oxidative injury. Cell culture studies have demonstrated that enhancing ferritin expression by targeting iron regulatory protein (IRP) binding activity reduces cellular vulnerability to iron and hemoglobin. In order to assess the therapeutic potential of this approach after striatal ICH, the effect of IRP1 or IRP2 gene knockout on ferritin expression and injury was quantified. Striatal ferritin in IRP1 knockout mice was similar to that in wild-type controls 3 days after stereotactic injection of artificial CSF or autologous blood. Corresponding levels in IRP2 knockouts were increased by 11-fold and 8.4-fold, respectively, compared with wild-type. Protein carbonylation, a sensitive marker of hemoglobin neurotoxicity, was increased by 2.4-fold in blood-injected wild-type striata, was not altered by IRP1 knockout, but was reduced by approximately 60% by IRP2 knockout. Perihematomal cell viability in wild-type mice, assessed by MTT assay, was approximately half of that in contralateral striata at 3 days, and was significantly increased in IRP2 knockouts but not in IRP1 knockouts. Protection was also observed when hemorrhage was induced by collagenase injection. These results suggest that IRP2 binding activity reduces ferritin expression in the striatum after ICH, preventing an optimal response to elevated local iron concentrations. IRP2 binding activity may be a novel therapeutic target after hemorrhagic CNS injuries.
Chen
Mai
M
Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107, USA.
Awe
Olatilewa O
OO
Chen-Roetling
Jing
J
Regan
Raymond F
RF
D000818:Animals; D002470:Cell Survival; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005293:Ferritins / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000172:deficiency / Q000235:genetics*; D035942:Iron Regulatory Protein 2 / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D050050:Protein Carbonylation
D006454:Hemoglobins; D005293:Ferritins; D007501:Iron; D017364:Collagenases; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2
J Pharmacol Exp Ther. 2009 Sep;330(3):679-86
19509317
J Neuropathol Exp Neurol. 2004 Jun;63(6):587-97
15217087
Stroke. 2009 May;40(5):1858-63
19286595
J Neurosci Res. 2008 Nov 1;86(14):3240-5
18615643
Stroke. 2010 Feb;41(2):375-82
20044521
Pediatrics. 1965 Sep;36(3):322-35
5829325
BMC Neurosci. 2001;2:5
11319941
J Clin Invest. 1981 Sep;68(3):672-7
7276166
J Biol Chem. 1995 Sep 15;270(37):21645-51
7665579
Mol Cell Biol. 2007 Apr;27(7):2423-30
17242182
Stroke. 2003 Dec;34(12):2964-9
14615611
Brain Res. 2010 Jan 14;1309:95-103
19879860
Free Radic Biol Med. 2003 Oct 15;35(8):872-81
14556851
J Neurosurg. 2002 Feb;96(2):287-93
11838803
Biochim Biophys Acta. 1988 Sep 15;944(1):29-39
3415998
J Cereb Blood Flow Metab. 2004 Oct;24(10):1133-45
15529013
J Biol Chem. 2007 Aug 24;282(34):24650-9
17604281
J Biol Chem. 1989 May 5;264(13):7498-504
2708374
Biochem Biophys Res Commun. 2008 Oct 10;375(1):6-10
18655771
Blood Cells Mol Dis. 2006 Mar-Apr;36(2):283-7
16480904
EMBO J. 2004 Jan 28;23(2):386-95
14726953
Free Radic Biol Med. 2002 Apr 1;32(7):568-76
11909691
J Pharm Pharmacol. 1999 Feb;51(2):131-4
10217310
Methods Enzymol. 1994;233:346-57
8015469
Glia. 2010 Jan 1;58(1):55-65
19533605
J Neurosurg. 2007 Mar;106(3):428-35
17367065
Biochim Biophys Acta. 2004 May 3;1691(2-3):151-9
15110995
J Nutr. 2007 Dec;137(12):2686-90
18029484
Neuropathol Appl Neurobiol. 1980 Jan-Feb;6(1):51-68
7374912
Pediatrics. 1966 Jul;38(1):102-10
5937669
Biochem J. 2000 Jun 1;348 Pt 2:315-20
10816424
Nat Genet. 2006 Sep;38(9):967-9; discussion 969-70
16940998
Free Radic Biol Med. 2002 Aug 15;33(4):457-63
12160928
J Clin Invest. 1987 Feb;79(2):662-4
3027133
Nat Genet. 2001 Feb;27(2):209-14
11175792
Stroke. 2009 Jun;40(6):2241-3
19372448
Proc Natl Acad Sci U S A. 1989 Dec;86(24):10108-12
2481311
J Neurosurg. 2004 Apr;100(4):672-8
15070122
Redox Rep. 2009;14(6):228-35
20003707
Amino Acids. 2003 Dec;25(3-4):207-18
14661084
J Cereb Blood Flow Metab. 2005 Nov;25(11):1466-75
15902196
Neurobiol Dis. 2008 Aug;31(2):242-9
18571425