title: Oxygen deprivation triggers upregulation of early growth response-1 by the receptor for advanced glycation end products.
abstract: Myocardial infarction, stroke, and venous thromboembolism are characterized by oxygen deprivation. In hypoxia, biological responses are activated that evoke tissue damage. Rapid activation of early growth response-1 in hypoxia upregulates fundamental inflammatory and prothrombotic stress genes. We probed the mechanisms mediating regulation of early growth response-1 and demonstrate that hypoxia stimulates brisk generation of advanced glycation end products (AGEs) by endothelial cells. Via AGE interaction with their chief signaling receptor, RAGE, membrane translocation of protein kinase C-betaII occurs, provoking phosphorylation of c-Jun NH(2)-terminal kinase and increased transcription of early growth response-1 and its downstream target genes. These findings identify RAGE as a master regulator of tissue stress elicited by hypoxia and highlight this receptor as a central therapeutic target to suppress the tissue injury-provoking effects of oxygen deprivation.
authors.affiliation: Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jong Sun
authors.initials: JS
authors.lastname: Chang
authors.forename: Thoralf
authors.initials: T
authors.lastname: Wendt
authors.forename: Wu
authors.initials: W
authors.lastname: Qu
authors.forename: Linghua
authors.initials: L
authors.lastname: Kong
authors.forename: Yu Shan
authors.initials: YS
authors.lastname: Zou
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Yan
mesh_terms: D000818:Animals; D001011:Aorta; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic