Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation.
Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space and the central nervous system. The low-density lipoprotein receptor-related protein (LRP) is a member of the low-density lipoprotein receptor gene family found in neurons and astrocytes. Cerebral ischemia induces activation of the nuclear factor (NF)-kappaB pathway. The present study investigated the role that the interaction between tPA and LRP plays on middle cerebral artery occlusion (MCAO)-induced NF-kappaB-mediated inflammatory response. We found that MCAO increased LRP expression primarily in astrocytes and that this effect was significantly decreased in the absence of tPA. The onset of the ischemic insult induced activation of the NF-kappaB pathway in wild-type and plasminogen (Plg(-/-))-deficient mice, and this effect was attenuated after inhibition of LRP or genetic deficiency of tPA. Moreover, administration of tPA to tPA(-/-) mice resulted in activation of the NF-kappaB pathway comparable with that observed in wild-type and Plg(-/-) mice. We also report that inhibition of either tPA activity or LRP or genetic deficiency of tPA resulted in a significant decrease in MCAO-induced nitric oxide production and inducible nitric-oxide synthase expression. In conclusion, our results demonstrate that after MCAO the interaction between tPA and LRP results in NF-kappaB activation in astrocytes and induction of inducible nitric-oxide synthase expression in the ischemic tissue, suggesting a cytokine-like plasminogen-independent role for tPA during cerebral ischemia.
Zhang
Xiaohui
X
Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Whitehead Biomedical Research Bldg., 615 Michael St., Suite 505J, Atlanta, GA 30322, USA.
Polavarapu
Rohini
R
She
Hua
H
Mao
Zixu
Z
Yepes
Manuel
M
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010958:Plasminogen / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D026502:LDL-Receptor Related Proteins; D016328:NF-kappa B; D009569:Nitric Oxide; D010958:Plasminogen; D052247:Nitric Oxide Synthase Type II; D010959:Tissue Plasminogen Activator
Science. 2003 Apr 11;300(5617):329-32
12690199
Blood. 2007 Apr 15;109(8):3270-8
17170123
Exp Neurol. 2003 Aug;182(2):446-54
12895455
J Cereb Blood Flow Metab. 2003 Aug;23(8):879-94
12902832
J Neurosci. 2003 Aug 13;23(19):7368-75
12917371
Nat Med. 2003 Oct;9(10):1313-7
12960961
J Clin Invest. 2003 Nov;112(10):1533-40
14617754
Stroke. 2004 Apr;35(4):987-91
14988572
Nat Rev Mol Cell Biol. 2004 May;5(5):392-401
15122352
Cancer Treat Res. 2004;119:139-73
15164877
Brain Res. 2004 Sep 10;1020(1-2):173-7
15312800
Science. 1981 Sep 25;213(4515):1532-4
7197054
Proc Natl Acad Sci U S A. 1981 Dec;78(12):7810-4
6950420
Science. 1985 Dec 13;230(4731):1289-92
3934754
Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810-4
2762297
J Neurochem. 1990 Jul;55(1):349-51
2113082
J Biol Chem. 1990 Oct 15;265(29):17401-4
1698775
Am J Pathol. 1992 Jul;141(1):37-42
1632469
J Cereb Blood Flow Metab. 2005 Jan;25(1):30-40
15678110
J Biol Chem. 1992 Aug 5;267(22):15595-602
1322401
Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7427-31
1502154
Brain Res. 1992 Aug 7;587(2):250-6
1381982
J Biol Chem. 1994 Feb 18;269(7):4705-8
7508926
Nature. 1995 Sep 28;377(6547):340-4
7566088
N Engl J Med. 1995 Dec 14;333(24):1581-7
7477192
Science. 1995 Dec 22;270(5244):1992-4
8533091
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6258-63
8692802
Brain Res. 1996 Apr 1;714(1-2):135-44
8861618
Cell. 1996 Nov 15;87(4):709-19
8929539
Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9779-81
9275201
J Neurosci. 1997 Jan 15;17(2):543-52
8987777
J Neurosci. 1997 Dec 1;17(23):9157-64
9364062
Glia. 1997 Dec;21(4):370-9
9419012
Nat Med. 1998 Feb;4(2):228-31
9461198
Lab Invest. 1998 Nov;78(11):1405-13
9840615
Nat Med. 1999 May;5(5):554-9
10229233
Circulation. 1999 May 11;99(18):2440-4
10318667
Trends Neurosci. 1999 Sep;22(9):391-7
10441299
J Neurochem. 1999 Oct;73(4):1461-6
10501190
J Neurosci. 2000 Jan 15;20(2):542-9
10632583
J Neurochem. 2000 Feb;74(2):443-56
10646495
J Cereb Blood Flow Metab. 2000 Mar;20(3):592-603
10724123
Blood. 2000 Jul 15;96(2):569-76
10887120
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11551-6
11016955
Curr Opin Neurol. 2001 Feb;14(1):89-94
11176223
J Clin Invest. 2001 Feb;107(3):247-54
11160145
Neuron. 2001 Mar;29(3):571-81
11301018
J Clin Invest. 2001 Sep;108(6):779-84
11560943
Mol Cell Neurosci. 2001 Nov;18(5):443-57
11922137
Life Sci. 2002 Sep 13;71(17):1985-96
12175893
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
J Biol Chem. 2002 Oct 25;277(43):40499-504
12171938
Biochem Biophys Res Commun. 2002 Nov 22;299(1):14-7
12435382
Blood. 2005 May 1;105(9):3545-51
15591119
Glia. 2005 Jun;50(4):417-26
15846796
Circulation. 2005 May 3;111(17):2241-9
15851587
Stroke. 2005 May;36(5):1065-70
15817895
J Neurosci. 2005 Nov 2;25(44):10094-100
16267216
J Cell Sci. 2006 Jan 15;119(Pt 2):339-49
16410551
J Biol Chem. 2006 Jan 27;281(4):2120-7
16303771
J Biol Chem. 2006 Mar 17;281(11):7332-40
16407289
J Cereb Blood Flow Metab. 2007 Mar;27(3):534-44
16835630
Lab Invest. 2003 Jul;83(7):1025-32
12861042