Loss of the aryl hydrocarbon receptor induces hypoxemia, endothelin-1, and systemic hypertension at modest altitude.
The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that mediates induction of metabolic enzymes and toxicity of certain environmental pollutants. Although AHR knockout (KO) mice develop cardiac hypertrophy, conflicting reports associate this pathology with hypotension or endothelin (ET)-1-dependent hypertension. Because hypertension occurred at modest altitude, we tested the hypothesis that loss of AHR increases the sensitivity to hypoxia-induced ET-1, contributing to systemic hypertension. We found that AHR KO mice were hypertensive at modest altitude (1632 m) but hypotensive at low altitude (225 m). When AHR KO mice residing at 1632 m were exposed to the partial pressure of inspired oxygen (PIO(2)) at sea level for 11 days, blood pressure declined to levels measured at 225 m. Although plasma ET-1 in AHR KO mice was significantly elevated at 1632 m and decreased at 225 m and sea level PIO(2), pulmonary prepro-ET-1 mRNA was significantly reduced at 1632 m and decreased further at 225 m and sea level PIO(2). Blood gas analysis revealed that AHR KO mice were hypoxemic, hypercapnic, and acidotic at 1632 m, values that were attenuated and normalized after 24 hours and 11 days under sea level PIO(2), respectively. Lastly, AHR inactivation in endothelial cells by small interfering RNA significantly reduced basal prepro-ET-1 mRNA but did not alter hypoxia-induced expression. Our studies establish the AHR KO mouse as a model in which modest decreases in PIO(2) lead to hypoxemia, increased plasma ET-1, and systemic hypertension without increased pulmonary prepro-ET-1 mRNA expression.
Lund
Amie K
AK
College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, USA.
Agbor
Larry N
LN
Zhang
Nan
N
Baker
Amy
A
Zhao
Huawei
H
Fink
Gregory D
GD
Kanagy
Nancy L
NL
Walker
Mary K
MK
D000531:Altitude; D000818:Animals; D001784:Blood Gas Analysis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D019332:Endothelin-1; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D010100:Oxygen