Growth hormone suppression in endothelial dysfunction

ABSTRACT

Growth Hormone-Releasing Hormone and Somatostatin exert opposing activities in Growth Hormone (GH) regulation. Herein – and based on recent findings – we provide our insights on the potential therapeutic role of GH suppression on endothelium-dependent disorders.

The endothelium is essential for normal respiratory function. Recent evidence suggests that neuropeptides – such as Growth Hormone – Releasing Hormone (GHRH) [1] and somatostatin (SST) – regulate its function [2,3]. GHRH is a 44-amino acid peptide, produced by the hypothalamus. Pituitary-type GHRH receptors (GHRH-R) mediate GH secretion, which in turn promotes IGF-I release primarily from the liver [4]. The expression of the GHRH-R is not limited to the pituitary gland [5]. Splice variants of GHRH-R exist in the breast, prostate, and the lungs. It has been reported that they possess ligand-independent activities, promoting cancer cell proliferation and metastasis [6,7].

Somatostatin, which exists as a 14- or 28-amino acid peptide, it is synthesized in the hypothalamus and in the delta cells of pancreas. Five types of somatostatin receptors (SSTR1–5) mediate the effects of somatostatin in brain and peripheral regions; including the pancreatic islets, stomach, kidney, liver, and blood vessels. Interestingly, receptors for both somatostatin and GHRH exist in ocular tissues [8,9].

Excessive GH secretion has been long associated with cancer, and therapeutic strategies based on inhibiting GH activity have been applied in endocrinology and oncology [10]. GHRH antagonists (GHRHAnt) and synthetic somatostatin analogs (SSA) have been developed and tested against GH-dependent abnormalities. SSA are FDA-approved for treatment of neuroendocrine tumors and acromegaly with minimal side effects, whereas preclinical studies suggest that GHRHAnt exerts anti-cancer and anti-oxidative activities [3]. GH suppression ameliorates inflammation in endothelial tissues [11–21].

Endothelial dysregulation can cause irreversible damage to the brain, eye, and lung; causing abnormalities related to stroke, keratitis, acute respiratory distress syndrome (ARDS) and sepsis [22,23]. Corticosteroids have been efficiently used in lung inflammatory disease but are associated with significant side effects in immune system responses and bone integrity [24]. Both GHRHAnt and SSA enhance barrier function, prevent vascular leak [10,25–28]; and suppress reactive oxygen species generation and cytoskeletal remodeling. [12,29–31].

Octreotide is a first-generation somatostatin analog which binds mainly to SSTR2 and SSTR5 [2] and has been used successfully in the clinics for acromegaly and neuroendocrine tumor treatment. Recent studies which aimed to elucidate the potential beneficial effects of Octreotide in endothelial dysfunction suggested that unfolded protein response (UPR) is involved in the beneficial effects of the aforementioned octapeptide in endothelial cells and tissues [32]. It was recently reported that Lanreotide – which is an analog with similar properties to Octreotide – protects endothelial cells and mouse tissues from LPS-induced injury without affecting cell viability. In particular, it counteracted LPS-induced actin cytoskeletal remodeling as well as the activation of inflammatory molecules and transcription factors (ERK1/2, STAT1, STAT3, p38) [33]. Pasireotide is a multi-receptor analog, which exerts similar protective activities in endothelial tissues [34].

UPR is important for homeostasis, since it orchestrates tissue repairing processes by promoting transcriptional responses, organelle production and cell repair. If irreparable damage occurs, it will cause programmed cell death [35]. Activating transcription factor 6 (ATF6) is an important UPR sensor, which is crucial for endothelial barrier function, since its targeted modulation regulates barrier permeability [36]. Moreover, ATF6 is involved in the beneficial effects of Octreotide in the inflamed endothelium [29,30], adding content to previous information on its protective effects against widespread disease [37]. The exact interrelations of UPR and somatostatin receptors in the endothelium are currently under investigation, as well as the involvement of NEK2 in that context.

NEKs are kinases essential for division and are involved in crucial cellular processes [38] which include defense and stress responses. NEK2 is of particular interest in the pathophysiology of vascular disorders, since its inhibition alleviates lung inflammatory disease, LPS-induced injury [39,40]; and degrades P53 via phosphorylation. P53 has been previously shown in in vitro and in vivo experimental models of lung injury, both direct and indirect, to maintain permeability balance via GTPase modulation [41,42]. The ability of NEK2 to directly regulate VEGF integrity in endothelial tissues is to be investigated.

Funding Statement

NB is supported by NIAID/NIH [Grant ID: R03AI176433] and NIGMS/NIH [Grant ID: P20GM103424–21]. The content is solely the responsibility of the author and does not necessarily represent the NIH official views.

Disclosure statement

No potential conflict of interest was reported by the author(s).