Selective cerebral overexpression of growth hormone alters cardiac function, morphology, energy metabolism and catecholamines in transgenic mice.
BACKGROUND
Growth hormone (GH) has important regulatory effects on cardiac morphology and function both during normal development as well as in pathophysiological settings such as myocardial infarction (MI) and congestive heart failure (CHF). In order to investigate in more detail the interaction between GH and sympathetic nervous system (SNS) system we studied the effects of selective cerebral GH overexpression on myocardial content of catecholamines, myocardial and brain energy metabolism as well as on cardiac function during resting and stress conditions in a transgenic mouse model.


METHODS
Transgenic mice with selective bovine GH overexpression under control of glial fibrillary acidic protein promoter in the brain (GFAP-bGH, n=15) were created and compared to genetically matched non-transgenic mates (Control, n=15). Cardiac morphology and function were evaluated in vivo using transthoracic echocardiography during resting and stress conditions induced pharmacologically by dopamine (D) and isoprotenolol (ISO). Myocardial and brain energy metabolism were evaluated non-invasively using in vivo volume-selective phosphorus magnetic resonance spectroscopy ((31)P MRS). Myocardial content of catecholamines was analyzed by means of HPLC.


RESULTS
Compared to the C animals, the GFAP-bGH mice have showed several differences in the cardiac phenotype. Systolic (fractional shortening) and diastolic function (E/A wave ratio of mitral flow) was disturbed in the GFAP-bGH mice (both p<0.05). During the dopamine stress, there was chronotropic insufficiency in the GFAP-bGH group (p<0.01) while no difference was observed in response to isoprotenolol. Left ventricular dimensions were increased in GFAP-bGH mice (p<0.05). There was a tendency for higher body weight in GFAP-bGH compared to the control group (p=0.06) while no difference was observed in heart weight and brain weight when normalized for body weight. Myocardial content of noradrenaline was lower in the GFAP-bGH group (p<0.05). PCr/ATP ratio was higher (p<0.05) in the brain and lower in the heart (p<0.05) in the GFAP-bGH mice.


CONCLUSIONS
Selective cerebral overexpression of GH results in alterations of cardiac function, morphology and metabolism in transgenic mice. Decreased myocardial content of catecholamines in the GFAP-bGH mice suggests central interaction between GH and sympathetic nervous system.
Bohlooly-Y
M
M
AstraZeneca Transgenic and Comparative Genomics Centre, Mölndal, Sweden.
Bollano
E
E
Mobini
R
R
Soussi
B
B
Tornell
J
J
Omerovic
E
E
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D004452:Echocardiography; D004734:Energy Metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D013006:Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D007545:Isoproterenol / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D013312:Stress, Physiological / Q000000981:diagnostic imaging / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000503:physiopathology*
D002395:Catecholamines; D005904:Glial Fibrillary Acidic Protein; D013006:Growth Hormone; D007545:Isoproterenol; D004298:Dopamine