Ghrelin in cardiovascular disease and atherogenesis

Abstract

Although initially associated with regulation of appetite, the cardiovascular system has also been recognized as a potentially important target for ghrelin. Moreover, a limited number of clinical studies suggest a role for ghrelin in the treatment of congestive heart failure. So far reported cardiovascular effects of growth hormone secretagogues and/or ghrelin include lowering of peripheral resistance, either direct at the vascular level and/or by modulating sympathetic nervous activity. Other observed effects indicate possible improvement of contractility and cardioprotective effects both in vivo and in vitro.Taken together, these results offer an interesting perspective on the future where further studies aiming at evaluating a role of GHS and ghrelin in the treatment of cardiovascular disease are warranted.

Introduction

Growth hormone secretagogues (GHS) are small synthetic compounds, either peptides or non-peptides, with the ability to stimulate growth hormone (GH) secretion from the pituitary (Bowers et al., 1977). It has been demonstrated that GHS act mainly through the GHS receptor (GHS-R) which is a G-protein-coupled receptor with seven transmembrane domains (Howard et al., 1996). Studies using in situ hybridization have shown expression of the GHS-R in pituitary, hypothalamus and hippocampus and the identification of this orphan receptor prompted an active search for the natural ligand (Kojima and Kangawa, 2006). A couple of years later, the endogenous ligand for the GHS-R was purified from rat stomach and named ghrelin (Kojima et al., 1999). Ghrelin was identified as a 28-amino acid peptide with an n-octanoylation of the serine-3 residue and this modulation has been found to be critical for the classical effects of ghrelin (Kojima et al., 1999). The highest level of ghrelin expression is in the gastric mucosa, although expression at low levels has been found in multiple organs and tissues (Kojima et al., 1999).

Apart from the ability to stimulate GH secretion and to exert regulatory effects on appetite and metabolism, it has become increasingly evident that growth hormone secretagogues (GHS) and ghrelin have a number of effects on the cardiovascular system. The ghrelin system is present in both vascular and cardiac tissues, where it is implicated in various functions. Ghrelin has been shown to have protective effects by inhibiting cardiomyocyte and endothelial cell apoptosis (Baldanzi et al., 2002), and to improve left ventricular (LV) function during ischemia-reperfusion (I/R) injury (Frascarelli et al., 2003). In rats with heart failure (HF), ghrelin improves LV dysfunction and attenuates the development of cardiac cachexia (Nagaya et al., 2001b). Similarly, in short term studies, ghrelin improves cardiac function and decreases systemic vascular resistance in patients with chronic HF (Nagaya et al., 2001c). In the vasculature, ghrelin exerts vasodilatory effects (Nagaya et al., 2001a) and possibly anti-inflammatory effects that may be of potential importance for the development of atherosclerosis (Dixit et al., 2004).

The present article will give an overview of the main cardiovascular actions of GHS and also discuss potential central effects which may have importance for the regulation of vascular tonus. An interesting and intriguing feature of the cardiovascular effects of GHS is that they may be targeted directly to the heart and vasculature rather than being mediated by an increased growth hormone secretion. Evidence to suggest this is the finding of GHS binding sites on cardiomyocytes and the fact that some of the effects of GHS can be expressed also in the absence of GH (Pettersson et al., 2002). Finally, the potential use of GHS and ghrelin as therapeutic agents in heart failure and related cardiac cachexia will be discussed.