title: Aryl hydrocarbon receptor null mice develop cardiac hypertrophy and increased hypoxia-inducible factor-1alpha in the absence of cardiac hypoxia.
abstract: The aryl hydrocarbon receptor (AhR) is a member of the basic helix loop helix PAS (Per-ARNT-SIM) transcription family, which also includes hypoxiainducible factor-1alpha (HIF-1alpha) and its common dimerization partner AhR nuclear translocator (ARNT). Following ligand activation or hypoxia, AhR or HIF-1alpha, respectively, translocate into the nucleus, dimerize with ARNT, and regulate gene expression. 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-1alpha 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-1alpha 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-1alpha 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 not associated with myocardial hypoxia, but is correlated with increased cardiac HIF-1alpha protein and VEGF mRNA expression.
authors.affiliation: Molecular and Environmental Toxicology Center, Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Thackaberry
authors.forename: D M
authors.initials: DM
authors.lastname: Gabaldon
authors.forename: M K
authors.initials: MK
authors.lastname: Walker
authors.forename: S M
authors.initials: SM
authors.lastname: Smith
mesh_terms: D000367:Age Factors; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D001835:Body Weight; D024722:Cardiac Myosins / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006352:Heart Ventricles / Q000473:pathology; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008955:Models, Cardiovascular; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB; D009929:Organ Size; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013223:Statistics as Topic; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018994:Myosin Light Chains; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C107184:myosin light chain 2; D009320:Atrial Natriuretic Factor; D024722:Cardiac Myosins; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains