Ah Receptor Signaling Controls the Expression of Cardiac Development and Homeostasis Genes

Anthropogenic stressors activating aryl hydrocarbon (Ah) receptor signaling, including polychlorinated biphenyls, impair the adaptive corticosteroid response to stress, but the mechanisms involved are far from clear. Using Ah receptor agonist (β-naphthoflavone; BNF) and antagonist (resveratrol; RVT), we tested the hypothesis that steroidogenic pathway is a target for endocrine disruption by xenobiotics activating Ah receptor signaling. Trout (Oncorhynchus mykiss) were fed BNF (10 mg/kg·d), RVT (20 mg/kg·d) or a combination of both for 5 d, and subjected to a handling disturbance. BNF induced cytochrome P4501A1 expression in the interrenal tissue and liver, whereas this response was abolished by RVT, confirming Ah receptor activation. In control fish, handling disturbance transiently elevated plasma cortisol and glucose levels and transcript levels of interrenal steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side chain cleavage (P450scc) and 11β-hydroxylase over a 24-h period. BNF treatment attenuated this stressor-induced plasma and interrenal responses; these BNF-mediated responses were reverted back to the control levels in the presence of RVT. We further examined whether these in vivo impacts of BNF on steroidogenesis can be mimicked in vitro using interrenal tissue preparations. BNF depressed ACTH-mediated cortisol production, and this decrease corresponded with lower StAR and P450scc, but not 11β-hydroxylase mRNA abundance. RVT eliminated this BNF-mediated depression of interrenal corticosteroidogenesis in vitro. Altogether, xenobiotics activating Ah receptor signaling are steroidogenic disruptors, and the mode of action includes inhibition of StAR and P450scc, the rate-limiting steps in steroidogenesis.

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A Truncated Ah Receptor Blocks the Hypoxia and Estrogen Receptor Signaling Pathways: A Viable Approach for Breast Cancer Treatment

Molecular Pharmaceutics ◽

10.1021/mp0600438 ◽

2006 ◽

Vol 3 (6) ◽

pp. 695-703 ◽

Cited By ~ 13

Author(s):

Kyle A. Jensen ◽

Tony C. Luu ◽

William K. Chan

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Treatment ◽

Signaling Pathways ◽

Breast Cancer Treatment ◽

Ah Receptor ◽

Receptor Signaling ◽

Estrogen Receptor Signaling ◽

Viable Approach

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Abstract 542: Mice with Cardiomyocyte-Restricted IGF-1 Receptor Deletion Exhibit Diminished Cardiomyocyte Size and Resistance to Exercise-Induced Cardiac Hypertrophy

Circulation ◽

10.1161/circ.116.suppl_16.ii_96-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Jaetaek Kim ◽

Adam R Wende ◽

Crystal Sloan ◽

Benjamin E Wayment ◽

Sheldon E Litwin ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Cardiac Development ◽

Systolic Function ◽

Fold Increase ◽

Heart Weight ◽

Cardiomyocyte Hypertrophy ◽

Receptor Signaling ◽

Cross Sectional ◽

Akt Phosphorylation ◽

Physiological Cardiac Hypertrophy

Insulin-like growth factor 1 (IGF-1) and IGF-1 receptors are expressed in murine hearts, and IGF-1 receptor signaling in cardiac muscle has been proposed to play a role in growth, differentiation, and cell survival, but mechanisms by which IGF-1 modulates myocardial structure and function are only partially understood. To investigate the role of IGF-1 signaling on cardiac development and physiology, we generated mice with cardiomyocyte-restricted knockout of the IGF-1receptor (IGF-1R −/−) by crossing α-MHC-Cre mice with mice containing a floxed exon 3 of the IGF-1R gene. Ablation of IGF-1 receptors in cardiomyocytes did not alter baseline heart weight to tibia length (HW/TL) ratios at 8 weeks or 12 weeks of age. However, wheat germ agglutinin (WGA-FITC) staining revealed that myocyte cross-sectional area was reduced by 18.8% (P < 0.05). To define the contribution of IGF-1 receptor signaling in the development of physiological hypertrophy; mice [WT (n = 7) or IGF-1R −/− (n = 9)] were subjected to 4 weeks swim (Sw) training and compared with Sedentary (Sed) wild type (WT) (n = 5) or IGF-1R −/− (n = 7) mice. HW/TL ratios increased by 19.2% in WT animals after swim training (5.19 ± 0.26 vs. 6.18 ± 0.2, P < 0.05), but only by 5.5% in Sw IGF-1R −/− mice (5.58 ± 0.18 vs. 5.89 ± 0.22, P = 0.32) and the fold increase in HW/TL was significantly greater in Sw WT vs. Sw IGF-1R −/− (P < 0.05). Despite resistance to hypertrophy, cardiac systolic function assessed by ejection fraction was preserved in Sw IGF-1R −/− (before Sw 0.71 ± 0.02 vs. after Sw 0.67 ± 0.02, P = 0.12). Phosphorylation of Akt was significantly increased in both trained WT and IGF-1R−/− mice at Ser473 [fold-change 1.61 ± 0.09 (P < 0.05) and 2.11 ± 0.19 (P < 0.01), respectively] and Thr308 [2.42 ± 0.24 and 2.61 ± 0.59 (P < 0.01), respectively] vs. Sed. Surprisingly Ser (473) Akt phosphorylation was greater in Sw IGF-1R−/− vs. Sw WT (P < 0.05). These data define an essential role for IGF-1 signaling in mediating physiologic cardiomyocyte hypertrophy, and indicate that although Akt signaling might be necessary for mediating physiological cardiac hypertrophy it is not sufficient in the absence of myocardial IGF-1R signaling.

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