The role of the GH-IGF-I axis in the regulation of myocardial growth: from experimental models to human evidence.

Abstract

Growth hormone (GH) is a peptide hormone synthesized and secreted by the anterior pituitary gland. In normal conditions, its synthesis and secretion are strictly regulated by the integrated and coordinated actions of two hypothalamic neurohormones: GH releasing factor and GH inhibiting factor (i.e., somatostatin). The ratio between the hypothalamic secretion of these two factors represents the basic and dynamic mechanism by which neurologic as well as extraneurologic influences may functionally affect GH secretion under physiologic or pathophysiologic conditions (1). Biological effects of GH are mediated by the interaction with a specific transmembrane receptor (GHR), expressed in almost all cellular types. As a consequence of GH–GHR interaction on target tissues, GH may exert direct metabolic effects. However, the most relevant biological effects of GH are indirect and to a large extent mediated by the stimulation of expression of insulinlike growth factor-I (IGF-I), in the liver (endocrine action) and in peripheral tissues (autocrine/paracrine action). Only a small amount of liver-derived IGF-I circulates as a free hormone, which is responsible for the biological actions. Indeed, the bulk of circulating IGF-I is bound to its specific carrier proteins, called IGF-binding proteins (IGF-BPs), the most important of which seems to be IGF-BP-3, since it binds more than 95% of IGF-I in the blood (1, 2). Furthermore, the IGF-I/ IGF-BP-3 dimer forms a complex with another protein subunit, the acid-labile subunit, and in this ternary complex the IGF-I has a serum half-life of many hours. Both the acid-labile subunit and IGF-BP-3 are principally synthesized in the liver, and their serum concentrations are influenced by circulating GH levels. IGF-BPs serve not only to transport IGF-I in the circulation, but also to prolong its half-life, to modulate its tissue specificity, and to potentiate or neutralize its biological actions. Moreover, a number of studies have shown that IGF-BPs modify the biological effects of IGF-I on a variety of mammalian cells. The relative importance of circulating versus locally produced IGF-I in the anabolic and growth-promoting effects of GH has recently been addressed by Sjogren et al. and Yakar et al. (3, 4). By using a novel tissuespecific recombinant system, the two groups independently concluded that, although hepatic IGF-I is the major contributor to circulating IGF-I levels, it is not crucial for normal postnatal growth, providing direct evidence for the importance of an autocrine/paracrine role for IGF-I. In this scenario, a large body of evidence has accumulated to support the concept that the GH–IGF-I axis targets the heart (5–9). In particular, it has been demonstrated that GHRs are largely expressed in the myocardium (9) and that, by interacting with GH, they stimulate the local biosynthesis of IGF-I, which may act in an autocrine or paracrine manner by binding specifically to its high-affinity membrane-associated receptor (Fig. 1). In this regard, it has been shown that myocardial IGF-I expression and content strictly parallel circulating GH levels (5–8). Studies in both animals and humans have provided consistent evidence that the GH–IGF-I axis is involved in the regulation of myocardial structure and function. In particular, a large number of studies have consistently shown that GH and IGF-I are critically involved in the regulation of cardiomyocyte growth.