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Aryl hydrocarbon receptor null mice develop cardiac hypertrophy and increased hypoxia-inducible factor-1α in the absence of cardiac hypoxia

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Abstract

The aryl hydrocarbon receptor (AhR) is a member of the basic helix-loop-helix PAS (Per-ARNT-SIM) transcription family, which also includes hypoxia-inducible factor-1α (HIF-1α) and its common dimerization partner AhR nuclear translocator (ARNT). Following ligand activation or hypoxia, AhR or HIF-1α, respectively, translocate into the nucleus, dimerize with ARNT, and regulate gene expresion. Mice lacking the AhR have been shown previously to develop cardiac enlargement. In cardiac hypertrophy, it has been suggested that the myocardium becomes hypoxic, increasing HIF-1α stabilization and inducing coronary neovascularization, however, this mechanism has not been demonstrated in vivo. The purpose of this study was to investigate the cardiac enlargement reported in AhR−/− mice and to determine if it was associated with myocardial hypoxia and subsequent activation of the HIF-1α pathway. We found that AhR−/− mice develop significant cardiac hypertrophy at 5 mo. However, this cardiac hypertrophy was not associated with myocardial hypoxia. Despite this finding, cardiac hypertrophy in AhR−/− mice was associated with increased cardiac HIF-1α protein expression and increased mRNA expression of the neovascularization factor vascular endothelial growth factor (VEGF). These data demonstrate that the development of cardiac hypertrophy in AhR−/− mice is not associated with myocardial hypoxia, but is correlated with increased cardiac HIF-1α protein and VEGF mRNA expression.

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Authors and Affiliations

  1. Molecular and Environmental Toxicology Center, Department of Nutritional Sciences, University of Wisconsin, 53706, Madison, WI

    S. M. Smith

  2. College of Pharmacy, University of New Mexico, 2502 Marble NE, 87131, Albuquerque, NM

    E. A. Thackaberry, D. M. Gabaldon & M. K. Walker

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  1. E. A. Thackaberry
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  2. D. M. Gabaldon
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  3. M. K. Walker
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Correspondence to M. K. Walker.

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Thackaberry, E.A., Gabaldon, D.M., Walker, M.K. et al. Aryl hydrocarbon receptor null mice develop cardiac hypertrophy and increased hypoxia-inducible factor-1α in the absence of cardiac hypoxia. Cardiovasc Toxicol 2, 263–273 (2002). https://doi.org/10.1385/CT:2:4:263

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  • DOI: https://doi.org/10.1385/CT:2:4:263

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