title: Cardiac expression of adenine nucleotide translocase-1 in transgenic mice overexpressing bovine GH.
abstract: Heart hypertrophy is a common finding of acromegaly, a syndrome due to GH excess. Impairment of adenine nucleotide translocase-1 (ANT-1) gene, the main mitochondrial ADP/ATP exchanger, leads to cardiac hypertrophy. The aim of the study was to evaluate cardiac expression and the functional role of ANT-1 in 1- to 12-month-old transgenic mice overexpressing bovine GH (acromegalic mice, Acro) and littermate controls (wild-type mice, Wt). GH specificity of protein degree variation was assessed treating Acro with pegvisomant, a GH receptor competitor. Tissue levels of ANT-1, NF-kappaB, ATP, and lactic acid were evaluated by western blot, bioluminescence, and Fourier transform infrared spectroscopy respectively. The degree of ANT-1 expression was higher in 1-month-old Acro than in Wt (47+/-5% OD vs 33+/-4% OD, P<0 01). On the contrary, ANT-1 expression was lower in 3- to 12-month-old Acro than in Wt (P<0 03). Changes in ANT-1 expression were associated with consistent changes of cellular ATP content, increasing at 1 month (P<0 05) and reducing thereafter in Acro when compared with Wt (P<0 04). Treatment with pegvisomant abolished ANT-1 and ATP changes observed in 1- and 3-month-old Acro, thus supporting a GH-dependent mechanism. Reduced ATP generation in hypertrophied hearts of older Acro was associated with increased lactic acid levels suggesting that part of energy was due to glycolysis. Variations in ANT-1 expression were linked to GH through changes in NF-kappaB, the levels of which changed accordingly. In conclusion, 1-month-old acromegalic mice had increased ANT-1 expression and higher degree of ATP production. Long-standing disease was associated with a consistent reduction of ANT-1 and ATP tissue levels, which became GH-independent in older animals. This study demonstrated a direct effect of GH on key proteins involved in energy metabolism of acromegalic hearts.
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. f.bogazzi@endoc.med.unipi.it
authors.forename: Fausto
authors.initials: F
authors.lastname: Bogazzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Raggi
authors.forename: Federica
authors.initials: F
authors.lastname: Ultimieri
authors.forename: Dania
authors.initials: D
authors.lastname: Russo
authors.forename: Antonella
authors.initials: A
authors.lastname: Manariti
authors.forename: Aldo
authors.initials: A
authors.lastname: D'Alessio
authors.forename: Paolo
authors.initials: P
authors.lastname: Viacava
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fanelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gasperi
authors.forename: Luigi
authors.initials: L
authors.lastname: Bartalena
authors.forename: Enio
authors.initials: E
authors.lastname: Martino
mesh_terms: D000172:Acromegaly / Q000378:metabolism*; D033741:Adenine Nucleotide Translocator 1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D006332:Cardiomegaly / Q000378:metabolism*; D002417:Cattle; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D019382:Human Growth Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D019344:Lactic Acid / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors
chemical_list: D033741:Adenine Nucleotide Translocator 1; D006727:Hormone Antagonists; D016328:NF-kappa B; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D013006:Growth Hormone; C406545:pegvisomant