title: Transforming growth factor-beta1 elicits Nrf2-mediated antioxidant responses in aortic smooth muscle cells.
abstract: 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.
authors.affiliation: Cardiovascular Division, School of Medicine, King's College London, UK.
authors.forename: Adrian T
authors.initials: AT
authors.lastname: Churchman
authors.affiliation: Cardiovascular Division, School of Medicine, King's College London, UK.
authors.forename: Anila A
authors.initials: AA
authors.lastname: Anwar
authors.affiliation: Cardiovascular Division, School of Medicine, King's College London, UK.
authors.forename: Francois Y L
authors.initials: FYL
authors.lastname: Li
authors.affiliation: Department of Bioresources, Faculty of Agriculture, Yamagata University, Tsuruoka, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.affiliation: Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tuskuba, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Cardiovascular Division, School of Medicine, King's College London, UK.
authors.forename: Giovanni E
authors.initials: GE
authors.lastname: Mann
authors.affiliation: Cardiovascular Division, School of Medicine, King's College London, UK.
authors.forename: Richard C M
authors.initials: RCM
authors.lastname: Siow
mesh_terms: 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*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D053773:Transforming Growth Factor beta1
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