Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

Abstract

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. Key Words: blood pressure Ⅲ hypertension Ⅲ endothelin Ⅲ oxygen Ⅲ gene regulation T he aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to the basic helix-loophelix 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-pdioxin, 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 hypertension. 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 explanation 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 (hypoxiainducible factor-1␤), as well as other transactivators, and studies have shown that these 2 signal transduction pathways can exhibit reciprocal inhibitory cross-talk. 8,9 The mechanism by which this functional inter...

Role of the Aryl Hydrocarbon Receptor in the Immune Response Profile and Development of Pathology during Plasmodium berghei Anka Infection

“…1F). In agreement with the findings of a previous study, uninfected AhR-KO mice were found to have a slight decrease in hematocrit compared with WT mice (51).…”

Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells

“…Such a developmental role may be an evolutionarily conserved primary function of the AHR, a notion supported by the finding that unlike their vertebrate counterparts, AHR orthologs in invertebrates like the fruit fly D. melanogaster and the nematode C. elegans are not activated by xenobiotic ligands but control expression of homeotic genes involved in neuronal specification during development (Emmons et al, 1999; Hahn, 2002; Qin and Powell-Coffman, 2004; Kim et al, 2006). In mice, Ahr ablation leads to impaired vasculature in kidney, liver sinusoid, and eyes of the neonates (Lahvis et al, 2000) with an ensuing cardiovascular disease that might be directly or indirectly the principal cause of other Ahr deficit phenotypes, such as reduced liver size, patent ductus venosus , cardiac hypertrophy, hypertension, and fibrosis (Fernandez-Salguero et al, 1995; Fernandez-Salguero et al, 1997; Lund et al, 2003; Lahvis et al, 2005; Lund et al, 2008). …”

Role of CYP1A1 in Modulating the Vascular and Blood Pressure Benefits of Omega-3 Polyunsaturated Fatty Acids

“…Measurement of Blood Pressure, Heart Rate, and Activity by Radiotelemetry. Mean arterial blood pressure (MAP), heart rate (HR), and activity were measured using radiotelemetry (Data Sciences International, St. Paul, MN) in CYP1A1 WT and KO mice fed an n-3 or n-6 PUFA-enriched diet as previously described elsewhere (n 5 4-6 per genotype/diet) (Lund et al, 2008;Kopf et al, 2010;Agbor et al, 2012). Seven days after surgery, we recorded MAP, HR, and activity for 10 seconds every 15 minutes for 7 days before treatment with LNNA in the drinking water (250 mg/l) for 3 days (Duling et al, 2006).…”