In 1976, small
peptide growth hormone secretagogues (GHSs) were discovered and found to promote
growth hormone (GH) release from the pituitary. The GHS receptor (GHS-R) was subsequently cloned, and its endogenous
ligand ghrelin was later isolated from the stomach.
Ghrelin is a 28-amino
acid peptide, whose acylation is essential for binding to
GHS-R type 1a and for the endocrine functions, including stimulation of GH secretion and subsequent food intake. Unacylated
ghrelin, the other
ghrelin form, although devoid of GHS-R binding is an active
peptide, sharing many peripheral effects with acylated
ghrelin (AG). The
ghrelin system is broadly expressed in myocardial tissues, where it exerts different functions. Indeed,
ghrelin inhibits cardiomyocyte and endothelial cell apoptosis, and improves left ventricular (LV) function during
ischemia-reperfusion (I/R) injury. In rats with
heart failure (HF),
ghrelin improves
LV dysfunction and attenuates the development of cardiac
cachexia. Similarly,
ghrelin exerts vasodilatory effects in humans, improves cardiac function and decreases systemic vascular resistance in patients with chronic HF.
Obestatin is a recently identified
ghrelin gene
peptide. The physiological role of
obestatin and its binding to the putative GPR39 receptor are still unclear, although protective effects have been demonstrated in the pancreas and heart. Similarly to AG, the hypothalamic
peptide growth hormone-releasing hormone (GHRH) stimulates GH release from the pituitary, through binding to the
GHRH-receptor. Besides its proliferative effects in different cell types, at the cardiovascular level GHRH inhibits cardiomyocyte apoptosis, and reduces
infarct size in both isolated rat heart after I/R and in vivo after
myocardial infarction. Therefore, both
ghrelin and GHRH exert cardioprotective effects, which make them candidate targets for therapeutic intervention in cardiovascular dysfunctions.