Oxygen deprivation triggers upregulation of early growth response-1 by the receptor for advanced glycation end products.
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.
Chang
Jong Sun
JS
Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA.
Wendt
Thoralf
T
Qu
Wu
W
Kong
Linghua
L
Zou
Yu Shan
YS
Schmidt
Ann Marie
AM
Yan
Shi-Fang
SF
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
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic