Transforming growth factor-beta1 elicits Nrf2-mediated antioxidant responses in aortic smooth muscle cells.
The anti-inflammatory properties of transforming growth factor-beta(1) (TGF-beta(1)) account for its protection against atherosclerotic plaque rupture. This study investigates whether activation of the Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) transcription pathway is involved in TGF-beta(1) mediated induction of the antioxidant enzyme heme oxygenase-1 (HO-1) in smooth muscle cells (SMC). Human aortic smooth muscle cells (HAoSMC) or wild-type and Nrf2-deficient mouse (MAoSMC) aortic SMC were treated with TGF-beta(1) (2.5-10 ng/ml, 0-24 hrs). We report the first evidence that TGF-beta(1) induces Nrf2 mediated HO-1 expression and antioxidant response element activity, which was paralleled by enhanced superoxide production and expression of the NAD(P)H oxidase subunit p22(phox). TGF-beta(1) failed to induce HO-1 expression in MAoSMC derived from Nrf2-deficient mice, and HO-1 induction by TGF-beta(1) in HAoSMC was attenuated by inhibition of extracellular signal regulated kinase or c-jun-N-terminal kinase but not p38 mitogen activated protein kinase. Inhibition of NAD(P)H oxidase or scavenging of superoxide diminished HO-1 induction in response to TGF-beta(1). The oxidative stress agents glucose oxidase (GOx) and diethylmaleate enhanced TGF-beta(1) generation and HO-1 expression in HAoSMC, while antagonism of TGF-beta(1) signalling by adenoviral Smad7 overexpression attenuated their induction of HO-1. Pre-treatment of HAoSMC with TGF-beta(1) reduced nuclear translocation of the pro-apoptotic mediator p53 elicited by GOx. Our findings demonstrate that Nrf2 is a new target of TGF-beta(1) signalling in the vasculature which may contribute to the atheroprotective properties attributed to this growth factor.
Churchman
Adrian T
AT
Cardiovascular Division, School of Medicine, King's College London, UK.
Anwar
Anila A
AA
Cardiovascular Division, School of Medicine, King's College London, UK.
Li
Francois Y L
FYL
Cardiovascular Division, School of Medicine, King's College London, UK.
Sato
Hideyo
H
Department of Bioresources, Faculty of Agriculture, Yamagata University, Tsuruoka, Japan.
Ishii
Tetsuro
T
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tuskuba, Japan.
Mann
Giovanni E
GE
Cardiovascular Division, School of Medicine, King's College London, UK.
Siow
Richard C M
RCM
Cardiovascular Division, School of Medicine, King's College London, UK.
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053773:Transforming Growth Factor beta1
FASEB J. 2005 Aug;19(10):1216-9
16051687
Nat Med. 2000 Apr;6(4):422-8
10742149
Arterioscler Thromb Vasc Biol. 2002 Nov 1;22(11):1751-2
12426198
Free Radic Biol Med. 2004 Nov 15;37(10):1542-9
15477006
J Am Soc Nephrol. 2005 Mar;16(3):667-75
15677311
Am J Physiol Lung Cell Mol Physiol. 2002 Nov;283(5):L1094-102
12376363
Antioxid Redox Signal. 2002 Oct;4(5):845-54
12470513
Free Radic Biol Med. 2005 Feb 1;38(3):375-87
15629866
Br J Pharmacol. 1998 Dec;125(7):1437-44
9884071
Free Radic Biol Med. 2003 Jan 1;34(1):103-10
12498985
EMBO J. 1999 Nov 1;18(21):6027-36
10545114
Cardiovasc Res. 2007 Jul 15;75(2):381-9
17408602
J Biol Chem. 2005 Nov 11;280(45):37423-9
16144837
J Biol Chem. 2005 Sep 2;280(35):31172-81
15980430
J Biol Chem. 2000 Dec 22;275(51):39907-13
10986282
Free Radic Biol Med. 2001 Mar 15;30(6):603-12
11295358
Sci Signal. 2008 Jul 01;1(26):pe33
18594115
J Biol Chem. 2002 Nov 1;277(44):41507-16
12186866
Nat Med. 2003 Feb;9(2):183-90
12539038
Circulation. 1997 Nov 18;96(10):3602-9
9396461
Am J Physiol Renal Physiol. 2005 Oct;289(4):F816-25
16159901
Science. 2002 May 31;296(5573):1646-7
12040180
Arterioscler Thromb Vasc Biol. 2002 Jun 1;22(6):975-82
12067907
Oncogene. 2005 Aug 29;24(37):5742-50
16123807
FASEB J. 2000 Aug;14(11):1518-28
10928986
Circ Res. 2000 Mar 17;86(5):494-501
10720409
Stroke. 2004 Oct;35(10):2253-7
15297631
Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):341-7
15591224
Nature. 1997 Oct 9;389(6651):631-5
9335507
Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):399-404
14699019
FASEB J. 2005 Jul;19(9):1061-6
15985529
Oncogene. 1999 Dec 13;18(53):7656-65
10618705
Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1383-7
15860740
Am J Pathol. 1998 Mar;152(3):711-20
9502413
Cardiovasc Res. 1999 Feb;41(2):385-94
10341838
Circulation. 2001 Sep 25;104(13):1519-25
11571246
Circ Res. 2005 Oct 28;97(9):900-7
16179589
Free Radic Biol Med. 2006 Apr 15;40(8):1313-22
16631521
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16093-8
12456881
Oncogene. 2001 Feb 15;20(7):879-84
11314022
J Biol Chem. 2002 Nov 22;277(47):44765-71
12235164
Free Radic Biol Med. 2004 Jan 1;36(1):101-11
14732294
Circulation. 2003 Oct 21;108(16):1912-6
14568884
Annu Rev Pharmacol Toxicol. 1997;37:517-54
9131263
Cancer Res. 2007 Oct 1;67(19):9577-83
17909069
Curr Vasc Pharmacol. 2008 Jul;6(3):204-17
18673160
Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L661-L673
16227320
Curr Atheroscler Rep. 2000 Sep;2(5):422-9
11122774
Kidney Int. 2001 Jan;59(1):87-95
11135061
Annu Rev Pharmacol Toxicol. 2003;43:233-60
12359864
Am J Physiol. 1992 Jan;262(1 Pt 1):C50-8
1733234
Am J Physiol Lung Cell Mol Physiol. 2004 Sep;287(3):L515-24
15132952
Circ Res. 2000 Mar 17;86(5):514-9
10720412
Curr Opin Lipidol. 2002 Oct;13(5):523-9
12352016
Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):103-14
10708958
Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):76-87
16487040
Circulation. 2005 Aug 16;112(7):1008-15
16103255
Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):99-106
16487042
Circulation. 2002 Apr 30;105(17):2030-6
11980681
Circ Res. 2004 Mar 19;94(5):609-16
14752028
Circulation. 2004 Sep 28;110(13):1767-73
15364800
J Biol Chem. 2000 Dec 29;275(52):40904-9
11018038
J Biol Chem. 2005 Mar 18;280(11):10055-64
15647278
Free Radic Biol Med. 2005 Jul 15;39(2):227-36
15964514
Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):2027-34
16840713
Biochem Biophys Res Commun. 2004 Aug 13;321(1):132-7
15358225