Cardiovascular effects of growth hormone, IGF-I and growth hormone secretagogues

Abstract

Growth hormone (GH) may exert direct growth-promoting and metabolic actions on target tissues, but most of its effects are mediated by circulating (endocrine) or local (auto-/paracrine) insulin-like growth factor-I (IGF-I). The GH/IGF-I system has an important role during cardiac development and for maintaining the structure and function of the heart. Attention has recently been focused on the endogenous GH secretagogue ghrelin, which, besides amplification of GH secretion, has metabolic and possibly also cardiovascular effects. The aim of this thesis was to elucidate the relative importance of circulating IGF-I for cardiovascular function, to elucidate which genes are involved in the cardiac effects of GH, and to examine the cardiovascular effects of natural (ghrelin) and synthetic (hexarelin) GH secretagogues. We found that similar hemodynamic effects were evoked by GH and IGF-I in rats 4 weeks after myocardial infarction, including increased stroke volume and reduced peripheral resistance, supporting the notion of a role of IGF-I in mediating the cardiovascular actions of GH. Cardiovascular phenotyping of transgenic mice with liver-specific deletion of IGF-I (LI-IGF-I-/- mice) and approximately 80 per cent reduction of IGF-I levels in serum revealed that these mice have increased systolic blood pressure levels and impaired endothelium-dependent relaxation in resistance vessels. LI-IGF-I-/- mice also had reduced cardiac output and increased wall thickness of the heart, which probably reflects adaptations to the increased blood pressure. Two weeks of GH treatment in hypophysectomised rats increased circulating IGF-I, heart weight and stroke volume. When global gene expression of the GH-regulated genes (quantified in microarray) was correlated to stroke volume, genes involved in cardiac calcium-handling, hypertrophy and turnover of extracellular matrix showed the highest correlation coefficients. In particular, down-regulation of Na+/K+-ATPase and up-regulation of Na+/Ca2+-Exchanger by GH may contribute to increase cardiac contractility and/or hypertrophy. The synthetic GH secretagogue hexarelin decreased total peripheral peripheral resistance and increased cardiac output to a similar extent as GH in the rat model of myocardial infarction, despite unchanged body weight gain and levels of serum IGF-I. GH-independent cardiovascular effects of ghrelin were studied in hypophysectomised rats, showing that ghrelin decreased blood pressure but had no effects on cardiac output or gene regulation. In conclusion, the results presented in this thesis show that both circulating, liver-derived IGF-I and natural as well as synthetic GH secretagogues are major regulators of peripheral resistance. In contrast to its vascular actions, the cardiac effects of ghrelin seem to be dependent on its ability to release GH. Furthermore, we show that GH increases the mRNA expression of a broad range of genes in the heart in order to increase cardiac performance.