Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression.
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-alpha-induced monocyte chemoattractant protein (MCP)-1 and VCAM-1 mRNA and protein expression in a dose-dependent manner and inhibited TNF-alpha-induced monocytic U937 cell adhesion to HAECs. Nrf2 also inhibited IL-1beta-induced MCP-1 gene expression in human mesangial cells. Expression of Nrf2 inhibited TNF-alpha-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-alpha-induced NF-kappaB 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.
Chen
Xi-Lin
XL
Discovery Research, AtheroGenics, Incorporated, Alpharetta, GA 30004, USA. xchen@atherogenics.com
Dodd
Geraldine
G
Thomas
Suzanne
S
Zhang
Xiaolan
X
Wasserman
Martin A
MA
Rovin
Brad H
BH
Kunsch
Charles
C
D000975:Antioxidants / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D019610:Cytoprotection / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D051267:NF-E2-Related Factor 2 / Q000276:immunology*; D018384:Oxidative Stress / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D000975:Antioxidants; D016207:Cytokines; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human