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Transforming growth factor-beta1 elicits Nrf2-mediated antioxidant responses in aortic smooth muscle cells

Adrian T Churchman1, Anila A Anwar1, Francois Y L Li1

  • 1Cardiovascular Division, School of Medicine, King's College London, UK.

Journal of Cellular and Molecular Medicine
|August 14, 2009
PubMed

Insights

Transforming growth factor-beta(1) (TGF-beta(1)) activates the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway, inducing heme oxygenase-1 (HO-1) in smooth muscle cells. This mechanism contributes to TGF-beta(1)

Area of Science:

  • Vascular Biology
  • Molecular Medicine
  • Cellular Signaling

Background:

  • Transforming growth factor-beta(1) (TGF-beta(1)) exhibits anti-inflammatory effects, protecting against atherosclerotic plaque rupture.
  • The role of the Nrf2 (nuclear factor erythroid 2-related factor 2) pathway in TGF-beta(1)-mediated antioxidant responses in smooth muscle cells (SMC) is not fully understood.

Purpose of the Study:

  • To investigate if TGF-beta(1) induces heme oxygenase-1 (HO-1) expression in SMC via Nrf2 pathway activation.
  • To elucidate the signaling mechanisms involved in TGF-beta(1)-induced HO-1 expression.

Main Methods:

  • Human aortic smooth muscle cells (HAoSMC) and Nrf2-deficient mouse aortic SMC (MAoSMC) were treated with TGF-beta(1).
  • Assessed HO-1 expression, antioxidant response element (ARE) activity, superoxide production, and NAD(P)H oxidase subunit p22(phox) expression.
  • Utilized kinase inhibitors (ERK, JNK, p38), NAD(P)H oxidase inhibition, superoxide scavenging, and Smad7 overexpression to probe signaling pathways.

Main Results:

  • TGF-beta(1) induced Nrf2-mediated HO-1 expression and ARE activity in HAoSMC.
  • HO-1 induction by TGF-beta(1) was abolished in Nrf2-deficient MAoSMC.
  • TGF-beta(1) treatment enhanced superoxide production and p22(phox) expression.
  • HO-1 induction was dependent on extracellular signal regulated kinase (ERK) and c-jun N-terminal kinase (JNK) signaling, but not p38.
  • Inhibition of NAD(P)H oxidase or superoxide scavenging attenuated TGF-beta(1)-induced HO-1 expression.
  • Oxidative stress agents (GOx, diethylmaleate) enhanced TGF-beta(1) generation and HO-1 expression, which was blocked by Smad7.
  • TGF-beta(1) pre-treatment reduced p53 nuclear translocation induced by GOx.

Conclusions:

  • Nrf2 is a novel target of TGF-beta(1) signaling in vascular SMC.
  • TGF-beta(1)-induced HO-1 expression, mediated by Nrf2, contributes to antioxidant responses in the vasculature.
  • These findings suggest a mechanism by which TGF-beta(1) may exert atheroprotective effects.

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