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Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression

¹Discovery Research, AtheroGenics, Incorporated, Alpharetta, Georgia; and ²Department of Internal Medicine and Dorothy M. Davis Heart and Lung Research Institute, Ohio State University College of Medicine and Public Health, Columbus, Ohio

Submitted 16 June 2005 ; accepted in final form 30 November 2005

The antioxidant response element (ARE) is a transcriptional control element that mediates expression of a set of antioxidant proteins. NF-E2-related factor 2 (Nrf2) is a transcription factor that activates ARE-containing genes. In endothelial cells, the ARE-mediated genes are upregulated by atheroprotective laminar flow through a Nrf2-dependent mechanism. We tested the hypothesis that activation of ARE-regulated genes via adenovirus-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 monocyte chemoattractant protein (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 atheroprotective system for antioxidant protection and suppression of redox-sensitive inflammatory genes, suggesting that targeting the Nrf2/ARE pathway may represent a novel therapeutic approach for the treatment of inflammatory diseases such as atherosclerosis.

antioxidant response element; monocyte chemoattractant protein-1; vascular cell adhesion molecule-1; tumor necrosis factor-

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