Endothelial dysfunction in growth hormone transgenic mice

Abstract

Acromegaly [overproduction of GH (growth hormone)] is associated with cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH) develop hypertension and hypercholesterolaemia and could be a model for cardiovascular disease in acromegaly. The aims of the present study were to investigate the effects of excess GH on vascular function and to test whether oxidative stress affects endothelial function in bGH transgenic mice. We studied the ACh (acetylcholine)-induced relaxation response in aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female bGH transgenic mice and littermate control mice, without and with the addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase). Intracellular superoxide anion production in the vascular wall was estimated using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with 69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas endothelial function in aorta was intact in young but impaired in aged bGH transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries from young mice and in aortas from aged mice; however, MnTBAP did not correct endothelial dysfunction in carotid arteries from aged bGH transgenic mice. There was no difference in intracellular superoxide anion production between bGH transgenic mice and control mice, whereas mRNA expression of EC-SOD and eNOS was increased in aortas from young bGH transgenic mice compared with control mice (P < 0.05). We interpret these data to suggest that bGH overexpression is associated with a time- and vessel-specific deterioration in endothelial function, initially caused by increased oxidative stress and later by other alterations in vascular function.

Improvement of Endothelial Dysfunction in Acromegaly after Transsphenoidal Surgery

“…On the other hand, it has been reported that GH-deficit patients have a 1.9-fold higher risk of death from CVD than age-matched controls [18], and that decreased NO formation [19] and lower FMD [20] in these patients improved after treatment with recombinant human GH concomitanly with decreased visceral adipose tissue and improved lipid profile. It has been reported that bovine GH transgenic mice with chronic excess GH/IGF-1, develop hypertension and hypercholesterolemia associated with time-and vessel-specific deterioration of endothelial function [21]. Taken together, it is suggested that chronic GH and/or IGF-1 excess has an indirect deleterious effect on endothelial function by increasing serum cholesterol levels and elevating blood pressure.…”

Enhanced oxidative stress in GH-transgenic rat and acromegaly in humans

“…Previously, it was reported that plasma oxidized low density lipoprotein (oxLDL) was increased in patients with acromegaly [24]. In animal models, carotid arteries from bGH TG mice had an impaired ACh-induced relaxation response and the endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries, suggesting an involvement of ROS in the vascular dysfunction in bGH TG mice [25]. These data suggested that oxidative stress might be enhanced in acromegaly.…”

GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly

“…Then, Yarman et al . found higher thiobarbituric acid reactive substances (TBARS) levels in a group of newly diagnosed patients with acromegaly, and Andersson et al . associated GH overexpression with a time‐ and vessel‐specific deterioration in endothelial function, initially caused by increased oxidative stress in GH transgenic mice.…”