Published online before print October 25, 2007, doi: 10.1161/CIRCRESAHA.107.155143
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 3, 2007
Revised on October 5, 2007
Accepted on October 17, 2007
Hemin Upregulates Egr-1 Expression in Vascular Smooth Muscle Cells via ROS–ERK-1/2–Elk-1 and NF-
B
Rukhsana N. Hasan and Andrew I. Schafer *
From the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia. Present address for A.I.S.: Department of Medicine, Weill-Cornell Medical College, New York.
* To whom correspondence should be addressed. E-mail: ais2007{at}med.cornell.edu.
Reactive oxygen species (ROS) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis. One source of ROS in the vasculature is free heme released from hemoglobin. Because Egr-1, the regulator of cell proliferation and apoptosis, is also induced by oxidant stress and is likewise implicated in atherosclerosis, we examined the regulation of Egr-1 by heme in vascular smooth muscle cells (SMCs). Hemin increased Egr-1 expression (mRNA, protein) within 30 minutes and ERK-1/2 phosphorylation and nuclear translocation within 5 minutes. Inhibiting hemin-induced ERK-1/2 activation by U0126 (MAPK-inhibitor), the antioxidant N-acetyl cysteine, the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride, the superoxide scavenger tiron, or tricarbonyldichlororuthenium(II)-dimer (carbon-monoxide donor; CORM-2) blocked hemin-induced Egr-1 expression. Hemin activated Elk-1, SRF, and NF-
B and promoted their interaction with the Egr-1 promoter. Downregulating Elk-1 (via siRNA) or blocking NF-B activation (via BAY-11-7082) abolished hemin induction of Egr-1. Finally, hemin-induced Egr-1 bound the promoters of tissue factor (TF), Plasminogen Activator Inhibitor (PAI)-1, and NGF-1A Binding (NAB)-2, upregulating their expression, and increased the biochemical activity of TF and PAI-1. Upregulation of Egr-1 and its target genes by heme-induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis.
Key words: hemin • reactive oxygen species • Egr-1 • Elk-1 • NF-
B
Related Article:
- Heme–Egr-1: New Partners in Atherosclerotic Progression?
- Gregg Rokosh
Circ. Res. 2008 102: 6-8.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  C. Vecchione, A. Frati, A. Di Pardo, G. Cifelli, D. Carnevale, M. T. Gentile, R. Carangi, A. Landolfi, P. Carullo, U. Bettarini, et al. Tumor Necrosis Factor-{alpha} Mediates Hemolysis-Induced Vasoconstriction and the Cerebral Vasospasm Evoked by Subarachnoid Hemorrhage Hypertension, July 1, 2009; 54(1): 150 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bhattacharyya, S.-J. Chen, M. Wu, M. Warner-Blankenship, H. Ning, G. Lakos, Y. Mori, E. Chang, C. Nihijima, K. Takehara, et al. Smad-Independent Transforming Growth Factor-{beta} Regulation of Early Growth Response-1 and Sustained Expression in Fibrosis: Implications for Scleroderma Am. J. Pathol., October 1, 2008; 173(4): 1085 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Rokosh Heme Egr-1: New Partners in Atherosclerotic Progression? Circ. Res., January 4, 2008; 102(1): 6 - 8. [Full Text] [PDF]
|
|