Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

Lund, Amie K.; Goens, M. Beth; Nunez, B. A.; Walker, Mary

doi:10.1016/j.taap.2005.07.005

Cited by 65 publications

(43 citation statements)

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“…By using AhR knockout (AhR KO) mice, it has been demonstrated that AhR is essential not only for the induction of drug-metabolizing enzymes but also for most, if not all, of the toxicological effects caused by TCDD, including immunosuppression, thymic atrophy, teratogenesis, and hyperplasia (6,7,17,24), the mechanisms for which are largely unknown. Recently, careful investigation into the loss of functions in AhR KO mice has also revealed that AhR is involved in the normal development of several organs, including the liver, heart, vascular tissues, and reproductive organs (1,2,6,8,15,24). In addition, AhR has been found to play a key role in the differentiation of regulatory T cells Treg, Th17, and Th1 from naive CD4 T cells by regulating their expression of Foxp3 or by as-yet-unknown mechanisms (14,20,23,32).…”

mentioning

confidence: 99%

Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock

Sekine

Mimura

Oshima

et al. 2009

Molecular and Cellular Biology

151

144

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confidence: 99%

Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock

Sekine

Mimura

Oshima

et al. 2009

Molecular and Cellular Biology

151

144

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“…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.…”

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confidence: 99%

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

et al. 2008

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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...

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“…Of direct relevance to studies of renal function are experiments in which AHR -/-mice were found to have cardiac hypertrophy and elevated mean arterial pressure (Lund et aI., 2003;Lund et al, 2006). Hypertension correlated to increased in endothelin-1 and angiotensin II, k.nown regulators of cardiomyocyte hypertrophy (Gavras and Gavras, 2002;Yamazaki et aI., 1996).…”

Section: Discussionmentioning

confidence: 99%

“…A major theme of this dissertation revolves around the developmental deficits associated with disruption of WT1 signaling and differentiation resulting ... Lahvis et al, 2000;Lahvis et al, 2005;Lund et aI., 2003;Lund et a/., 2006;Schmidt et aI., 1996). Our discovery of AHR-dependent regulation of WT1, a known renal master switch transcription factor, is the first study to propose a direct mechanism for the role of AHR in ontogenesis ( Figure 3).…”

Section: Thy11 Merged Discussionmentioning

confidence: 99%

“…These changes can be reproduced by decreased AHR protein levels upon ligand binding . In addition, AHR -/-mice were found to have endothelin1 and angiotensin II mediated cardiac hypertrophy and elevated mean arterial pressure, conditions directly linked to impaired renal functions (Gavras and Gavras, 2002;Lund et a/., 2003;Lund et al, 2006;.…”

Section: Introductionmentioning

confidence: 99%

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Molecular interactions between the Wilms' tumor transcription factor and the aryl hydrocarbon receptor during nephrogenesis and its impact on fetal programming of renal disease.

Nañez¹

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Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice

Cited by 65 publications

References 30 publications

Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock

Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock

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

Molecular interactions between the Wilms' tumor transcription factor and the aryl hydrocarbon receptor during nephrogenesis and its impact on fetal programming of renal disease.

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