Churchman AT, Anwar AA, Li FY, Sato H, Ishii T, Mann GE, Siow RC
Transforming Growth Factorbeta-1 elicits Nrf2-mediated antioxidant responses in aortic smooth muscle cells. [JOURNAL ARTICLE]
J Cell Mol Med 2008 Dec 24.
The anti-inflammatory properties of transforming growth factorbeta-1 (TGFbeta-1) account for its protection against atherosclerotic plaque rupture. This study investigates whether activation of the Nrf2 transcription pathway is involved in TGFbeta-1 mediated induction of the antioxidant enzyme heme oxygenase-1 (HO-1) in smooth muscle cells (SMC). Human (HAoSMC) or wild-type and Nrf2 deficient mouse (MAoSMC) aortic SMC were treated with TGFbeta-1 (2.5-10 ng/ml, 0-24 h). We report the first evidence that TGFbeta-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). TGFbeta-1 failed to induce HO-1 expression in MAoSMC derived from Nrf2 deficient mice, and HO-1 induction by TGFbeta-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 TGFbeta-1. The oxidative stress agents glucose oxidase and diethylmaleate enhanced TGFbeta-1 generation and HO-1 expression in HAoSMC, while antagonism of TGF(-1 signalling by adenoviral Smad7 overexpression attenuated their induction of HO-1. Pretreatment of HAoSMC with TGF(-1 reduced nuclear translocation of the pro-apoptotic mediator p53 elicited by glucose oxidase. Our findings demonstrate that Nrf2 is a new target of TGFbeta-1 signalling in the vasculature which may contribute to the atheroprotective properties attributed to this growth factor.
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