Published online before print March 6, 2008, doi: 10.1161/CIRCRESAHA.107.165308
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Submitted on October 4, 2007
Revised on February 22, 2008
Accepted on February 26, 2008
Oxygen Deprivation Triggers Upregulation of Early Growth Response-1 by the Receptor for Advanced Glycation End Products
Jong Sun Chang ;
From the Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York.
* To whom correspondence should be addressed. E-mail: sy18{at}columbia.edu.
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-
II occurs, provoking phosphorylation of c-Jun NH2-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.
Key words: cardiovascular • endothelial cells • hypoxia • RAGE • signal transduction
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