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GHRH as a neurohormone
The existence of a growth hormone (GH)-releasing factor in hypothalamic extracts was shown some 50 years ago [1]. In 1981 it was demonstrated that pancreatic tumors could produce the neurohormone GHRH to cause acromegaly [2]. This breakthrough made possible the isolation and characterization of GHRH 3, 4, 5. Subsequently, the structure of this GHRH was shown to be identical to the hypothalamic peptide hormone that stimulates release of GH from the pituitary [6]. GH in pituitary cells is also
The structure and expression of GHRH
GHRH belongs to the secretin family of peptide hormones that also includes glucagon, secretin, pituitary adenylate-cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP) and others [7]. Evolutionarily, it is relatively well conserved with homologs being identified in rats, chicken and fish 24, 25, 26. Rat GHRH consists of 43 amino acids and differs from human GHRH at 15 positions. Porcine, bovine and various non-mammalian GHRH forms have been also identified [26].
Acceleration of wound healing by GHRH
Early studies showed that primary fibroblasts respond to GHRH [23]. Furthermore, GHRH and its agonistic analog, JI-38, accelerate the healing of cutaneous wounds in mice 43, 44. Initial evidence suggesting that GHRH regulates cell migration was provided in an in vitro ‘scratch’ assay for wound healing, in experiments using breast and ovarian cancer cells as well as glioblastomas [38]. In glioblastomas, the GHRH-mediated migration effect might be relevant for the oncogenic potential of the
GHRH and the myocardium
Although it was known that GHRH is expressed in the mouse heart [54] only recently has evidence for its activity been provided. In line with the cardioprotective action of ghrelin, which is also a GH-releasing peptide [55], GHRH was found to protect cardiomyocytes from apoptosis [56]. Tissue culture experiments showed that exposure to GHRH increased the survival of adult rat ventricular myocytes under serum-deprivation conditions and/or treatment with β-adrenergic receptor antagonists [56].
GHRH and pancreatic islet cells
Another role recently attributed to GHRH is the involvement in glucose homeostasis through mechanisms promoting of proliferation and survival of the pancreatic islet cells [62]. Exposure of rat insulinoma cells INS-1 to the GHRH agonist JI-36 caused a considerable stimulation in the rate of cell proliferation as well as a suppression of apoptosis. These observations are in line with a pro-survival role for GHRH on this cell type. These effects were accompanied by ultrastructural changes in
GHRH-regulated cellular functions
The prosurvival activity of GHRH, exemplified by stimulation of the proliferation of various types of cells, by the protection of the cells against apoptosis, or both these effects, appears to represent the common function of GHRH in a wide range of peripheral tissues. This mitogenic effect is also a direct result of GHRH that has been observed in somatotrophs and is associated with pituitary hyperplasia and adenoma development [63]. Inhibitory effects of GHRH antagonists on the rate of cell
Perspectives
Taken together, the cited activities of GHRH, in combination with its previously reported effects on the reproductive and immune system 31, 32, 33, 74, implicate this peptide hormone in a variety of cellular processes (Figure 2). Following the recently identified effects of GHRH in conditions involving tissue regeneration, such as the healing of cutaneous wounds, the proliferation and survival of pancreatic islets, and the restoration of heart function after myocardial infarction, we should
Acknowledgments
We would like to thank Professor N. Block (University of Miami) for critical reading of the manuscript. The studies reviewed herein were supported by grants from the Greek Ministry of Education/European Social Fund to H.K., and from the medical research service of the Department of Veterans Affairs and the Departments of Pathology and Medicine of the University of Miami, Miller School of Medicine, to A.V.S.
Copyright © 2011 Elsevier Ltd. All rights reserved.