Cardiovascular disease occurs in 1 in 4 adults and is the leading cause of death in the U.S. Endothelin-1 (ET- 1) is one factor that has been implicated in the pathogenesis of many of these diseases. ET-1 biosynthesis is regulated by gene transcription and hypoxia is one of the most potent stimuli. We propose that the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, influences oxygen-regulation of ET-1 expression and modulates the pathogenesis of ET-1-dependent cardiovascular diseases. When the AhR is genetically deleted, null mice under normoxic conditions exhibit elevated tissue preproET-1 mRNA and plasma ET-1, and develop cardiac hypertrophy. However, when AhR null mice are exposed to mild hypoxia (~1,500 m), ET-1 is induced further, the progression of cardiac hypertrophy is accelerated, and the mice become hypertensive. Additionally, AhR null mice exhibit increased angiotensin (Ang) II and reactive oxygen species under mild hypoxia, compare to wildtype mice. These data suggest that AhR influences basal and hypoxia-induced ET-1 expression and that both ET-1 and Ang II may mediate tissue pathologies under mild hypoxia. Thus, we will test the hypothesis that AhR suppresses basal and hypoxia-induced ET-1 transcription so that loss of AhR increases the sensitivity to hypoxia-induced ET-1 expression, leading to activation of the renin-angiotensin system (RAS), hypertension and organ damage via induction of reactive oxygen species (ROS).
In aim 1, we will establish the contribution of hypoxia-induced ET-1, RAS activation, and ROS production to tissue pathologies in AhR null mice. Studies in AhR null mice maintained under normoxia or mild hypoxia will compare RAS gene expression and enzyme activity; vascular, cardiac, and renal injury; and ROS production. The contribution of Ang II and ET-1 will be investigated using an ACE inhibitor/ETA receptor antagonist combination, while the contribution of ROS will be investigated using the superoxide. dismutase mimetic, tempol.
In aim 2, we will delineate the contribution of the AhR in endothelial cells to hypoxia-induced, ET-1-mediated RAS activation, hypertension, and organ damage by studying mice where AhR is deleted only in endothelial cells using Cre/Lox technology.
In aim 3, we will establish the mechanism by which AhR suppresses ET-1 transcription using transgenic mice that express luciferase under ET-1 promoter control and by conducting ET-1 promoter analysis in primary murine endothelial cells. Our results will define a novel regulatory pathway for suppression of hypoxia-induced ET- 1, which could be used to develop new therapies for ET-1-dependent cardiovascular diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL078914-01A2
Application #
7105401
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2006-03-03
Project End
2011-02-28
Budget Start
2006-03-03
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$384,900
Indirect Cost
Name
University of New Mexico
Department
Type
Schools of Pharmacy
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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