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Circulation Research. 2008;102:905-913
Published online before print March 6, 2008, doi: 10.1161/CIRCRESAHA.107.165308
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(Circulation Research. 2008;102:905.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Oxygen Deprivation Triggers Upregulation of Early Growth Response-1 by the Receptor for Advanced Glycation End Products

Jong Sun Chang, Thoralf Wendt, Wu Qu, Linghua Kong, Yu Shan Zou, Ann Marie Schmidt, Shi-Fang Yan

From the Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York.

Correspondence to Dr Shi-Fang Yan, Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W 168th St, New York, NY 10032. 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-βII 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


Related Article:

Living on the Edge: Hypoxia-Induced Tissue Damage
Evren Caglayan and Stephan Rosenkranz
Circ. Res. 2008 102: 864-865. [Full Text] [PDF]





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