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

@article{citeulike:3578531, abstract = {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-1[beta]-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-{kappa}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. 10.1152/ajpheart.00651.2005}, author = {Chen, Xi-Lin and Dodd, Geraldine and Thomas, Suzanne and Zhang, Xiaolan and Wasserman, Martin A. and Rovin, Brad H. and Kunsch, Charles}, citeulike-article-id = {3578531}, citeulike-linkout-0 = {http://dx.doi.org/10.1152/ajpheart.00651.2005}, citeulike-linkout-1 = {http://ajpheart.physiology.org/cgi/content/abstract/290/5/H1862}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16339837}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16339837}, day = {1}, doi = {10.1152/ajpheart.00651.2005}, journal = {Am J Physiol Heart Circ Physiol}, keywords = {endothelial\_cells, inflammatory\_gene\_expression, nrf2}, month = {May}, number = {5}, pages = {H1862--1870}, posted-at = {2008-12-26 17:06:15}, priority = {3}, title = {Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression}, url = {http://dx.doi.org/10.1152/ajpheart.00651.2005}, volume = {290}, year = {2006} }

TY - JOUR ID - citeulike:3578531 L3 - citeulike-article-id:3578531 N2 - 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-1[beta]-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-{kappa}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. 10.1152/ajpheart.00651.2005 IS - 5 JF - Am J Physiol Heart Circ Physiol EP - 1870 TI - Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression VL - 290 SP - H1862 KW - endothelial_cells KW - inflammatory_gene_expression KW - nrf2 AU - Chen, Xi-Lin AU - Dodd, Geraldine AU - Thomas, Suzanne AU - Zhang, Xiaolan AU - Wasserman, Martin AU - Rovin, Brad AU - Kunsch, Charles PY - 2006/05/01/ UR - http://dx.doi.org/10.1152/ajpheart.00651.2005 ER -