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1 Discovery Research, AtheroGenics, Inc., Alpharetta, GA, USA
2 Department of Medicine, Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: xchen{at}atherogenics.com.
The antioxidant response element (ARE) is a transcriptional control element that mediates expression of a set of antioxidant proteins. Nrf2 is a transcription factor that activates ARE-containing genes. In endothelial cells, the ARE-mediated genes are up-regulated by athero-protective laminar flow through Nrf2-dependent mechanism. We tested the hypothesis that activation of ARE-regulated genes via adenoviral-mediated expression of Nrf2 may suppress redox-sensitive inflammatory gene expression. Expression of Nrf2 in human aortic endothelial cells (HAECs) resulted in a marked increase in ARE-driven transcriptional activity and protected HAECs from H2O2-mediated cytotoxicity. Nrf2 suppressed TNF-
-induced MCP-1 and VCAM-1 mRNA and protein expression in a dose-dependent manner, and inhibited TNF--induced monocytic U937 cell adhesion to HAECs. Nrf2 also inhibited IL-1
-induced MCP-1 gene expression in human mesangial cells. Expression of Nrf2 inhibited TNF--induced activation of p38 MAP kinase. Furthermore, expression of a constitutively active form of MKK6 (an upstream kinase for p38 MAP kinase) partially reversed Nrf2-mediated inhibition of VCAM-1 expression, suggesting that p38 MAP kinase, at least in part, mediates Nrf2's anti-inflammatory action. In contrast, Nrf2 did not inhibit TNF--induced NF-
B activation. These data identify the Nrf2/ARE pathway as an endogenous athero-protective system for antioxidant protection and suppression of redox-sensitive inflammatory genes, suggesting that targets the Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of inflammatory diseases such as atherosclerosis.
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