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: Fausto Bogazzi, Francesco Raggi, Federica Ultimieri, Dania Russo, Antonella Manariti, Aldo D'Alessio, Paolo Viacava, Giovanni Fanelli, Maurizio Gasperi, Luigi Bartalena, Enio Martino
• Journal: The Journal of endocrinology (J Endocrinol) Vol. 194 Issue 3 Pg. 521-7 (Sep 2007) ISSN: 0022-0795 [Print] England
• PMID: 17761891 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenine Nucleotide Translocator 1
• Hormone Antagonists
• NF-kappa B
• Receptors, Somatotropin
• Human Growth Hormone
• Lactic Acid
• Adenosine Triphosphate
• Growth Hormone
• pegvisomant

Topics

• Acromegaly (metabolism)
• Adenine Nucleotide Translocator 1 (analysis, genetics, metabolism)
• Adenosine Triphosphate (analysis, metabolism)
• Animals
• Blotting, Western (methods)
• Cardiomegaly (metabolism)
• Cattle
• Growth Hormone (antagonists & inhibitors, genetics, metabolism)
• Hormone Antagonists (pharmacology)
• Human Growth Hormone (analogs & derivatives, pharmacology)
• Lactic Acid (analysis, metabolism)
• Mice
• Mice, Transgenic
• Models, Animal
• Myocardium (metabolism)
• NF-kappa B (analysis, metabolism)
• Receptors, Somatotropin (antagonists & inhibitors)
• Spectroscopy, Fourier Transform Infrared
• Time Factors