Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude Amie K. Lund, Larry N. Agbor, Nan Zhang, Amy Baker, Huawei Zhao, Gregory D. Fink, Nancy L. Kanagy, Mary K. Walker Abstract—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. (Hypertension. 2008;51:803-809.) Key Words: blood pressure  hypertension  endothelin  oxygen  gene regulation T he aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to the basic helix-loop- helix Per-Arnt-Sim family of DNA binding proteins, which also includes hypoxia-inducible factors. 1 Although the AHR is known to mediate induction of drug-metabolizing enzymes and toxicity after exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin, recent evidence has revealed a physiological role for AHR in cardiovascular homeostasis. AHR knockout (KO) mice develop cardiac hypertrophy, 2,3 which is mediated, in part, by elevated plasma angiotensin II and endothelin-1 (ET-1). 4,5 There are conflicting reports, however, of whether the cardiac hypertrophy is associated with systemic hyper- tension. Lund et al 4,5 reported that cardiac hypertrophy in AHR KO mice is preceded by hypertension, whereas Vasquez et al 6 and Ichihara et al 7 reported that AHR KO mice are hypotensive and normotensive, respectively. The expla- nation for the disparate blood pressure values among these studies is unclear. AHR and hypoxia-inducible factor-1 share a common dimerization partner, AHR nuclear translocator (hypoxia- inducible factor-1), as well as other transactivators, and studies have shown that these 2 signal transduction path- ways can exhibit reciprocal inhibitory cross-talk. 8,9 The mechanism by which this functional interference occurs is not clear, nor has the physiological relevance of these interactions been defined. If AHR functions physiological- ly to attenuate hypoxia-induced responses, then AHR KO mice might exhibit an increased sensitivity to hypoxia- mediated gene induction and changes in physiology. Evi- dence supporting this idea was published recently showing that AHR KO mice are more responsive to the induction of vascular endothelial growth factor and neovasculogenesis after hindlimb ischemia. 7 Because hypoxia is a potent stimulus of the vasoconstricting peptide, ET-1, 10,11 and because ET-1– dependent hypertension was reported in AHR KO mice residing at a modest altitude (Albuquerque, NM, 1632 m), we reasoned that the differences in blood pressure reported in AHR KO mice may result from differences in how the mice respond to changes in the partial pressure of inspired oxygen (PIO 2 ). Thus, we tested Received August 26, 2007; first decision September 18, 2007; revision accepted December 21, 2007. From the College of Pharmacy (A.K.L., L.N.A., N.Z., A.B., M.K.W.) and Department of Cell Biology and Physiology, School of Medicine (N.L.K., M.K.W.), University of New Mexico Health Sciences Center, Albuquerque; and the Department of Pharmacology and Toxicology (H.Z., G.D.F.), College of Human Medicine, Michigan State University, East Lansing. Correspondence to Mary K. Walker, College of Pharmacy, MSC09 5360, 2703 Frontier NE, University of New Mexico, Albuquerque, NM 87131. E-mail mwalker@salud.unm.edu © 2008 American Heart Association, Inc. Hypertension is available at http://hypertension.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.107.100586 803 Hypoxemia and Hypertension by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from by guest on December 30, 2015 http://hyper.ahajournals.org/ Downloaded from