ToxSci Advance Access published online on August 17, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi284
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA
* To whom correspondence should be addressed. The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor characterized to play a role in detection and adaptation to environmental stimuli. Genetic deletion of the AhR results in cardiac hypertrophy that is mediated primarily by endothelin-1 (ET-1). ET-1 has been implicated in the elevation of reactive oxygen species (ROS) in the heart, which are thought to contribute to several cardiovascular disorders, including cardiac hypertrophy. Thus, we tested the novel hypothesis that ET-1 induces ROS in AhR null mice via ETA receptor activation. We first confirmed the presence of ROS in the hearts of AhR null mice by measuring superoxide (O2•-)-dependent oxidation of dihydroethidium. Ethidium fluorescence was increased by 10 fold in the hearts of AhR null mice, compared to wildtype. Then, to elucidate whether ET-1 mediated the increase in ROS, mice were chronically treated with 100 ng/kg/day of ETA receptor antagonist, BQ-123. In AhR null mice, BQ-123 significantly reduced elevated plasma 8-isoprostane, a systemic endproduct of phospholipids oxidation by ROS, and cardiac thiobarbituric acid reactive substances (TBARS), a non-specific assessment of ROS production. Further, BQ-123 reduced both cardiac lucigenin chemiluminescence and cardiac mRNA expression of NAD(P)H oxidase subunits gp91phox, p47phox, and p67phox, in AhR null mice, compared to wildtype mice. These findings demonstrate that ET-1 activation of ETA receptors mediates an increase in ROS which is associated with cardiac hypertrophy in AhR null mice. Further, the ET-1-mediated increase in ROS appears to be mediated via induced NAD(P)H oxidase activity.
Received May 19, 2005
Accepted August 9, 2005
Systems Toxicology
Endothelin-1 - Mediated Increase in Reactive Oxygen Species and NADPH Oxidase Activity in Hearts of Aryl Hydrocarbon Receptor (AhR) Null Mice
2 College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA; Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA
Mary K. Walker, E-mail: mkwalker{at}unm.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Yao, I. Edirisinghe, S.-R. Yang, S. Rajendrasozhan, A. Kode, S. Caito, D. Adenuga, and I. Rahman Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice Am. J. Pathol., May 1, 2008; 172(5): 1222 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. McMillan and C. A. Bradfield The Aryl Hydrocarbon Receptor sans Xenobiotics: Endogenous Function in Genetic Model Systems Mol. Pharmacol., September 1, 2007; 72(3): 487 - 498. [Abstract] [Full Text] [PDF]
|
|