Involvement of the unfolded protein response in the protective effects of growth hormone releasing hormone antagonists i
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Involvement of the unfolded protein response in the protective effects of growth hormone releasing hormone antagonists in the lungs Mohammad S. Akhter1 · Mohammad A. Uddin1 · Andrew V. Schally2,3 · Khadeja‑Tul Kubra1 · Nektarios Barabutis1 Received: 27 October 2020 / Accepted: 1 November 2020 © The International CCN Society 2020
Abstract Growth hormone releasing hormone (GHRH) antagonists enhance endothelial barrier function and counteract the LPSinduced lung endothelial hyperpermeability, the cardinal feature of the acute respiratory distress syndrome (ARDS). The unfolded protein response (UPR) is a multifaceted molecular mechanism, strongly involved in tissue defense against injury. The current study introduces the induction of UPR by GHRH antagonists, since those peptides induced several UPR activation markers, including the inositol-requiring enzyme-1α (IRE1α), the protein kinase RNA-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). On the other hand, the GHRH agonist MR-409 exerted the opposite effects. Furthermore, GHRH antagonists counteracted the kifunensine (UPR suppressor)-induced lung endothelial barrier dysfunction. Our observations suggest that UPR mediates, at least in part, the protective effects of GHRH antagonists in the lung microvasculature. To the best of our knowledge; this is the first study to provide experimental evidence in support of the hypothesis that UPR induction is a novel mechanism by which GHRH antagonists oppose severe human disease, including ARDS. Keywords P53 · Lung injury · Endothelium · Vascular barrier · Inflammation
Introduction Growth hormone releasing hormone (GHRH) is a hypothalamic hormone which regulates the release of growth hormone (GH) from the anterior pituitary gland. The effects of GHRH are mediated by the pituitary type GHRH receptor (pGHRH-R), primarily expressed in the somatotrophs of the pituitary gland. Active splice variants of the human GHRHR have been identified in a diverse variety of human tissues, suggesting that the effects of GHRH in human physiology are not limited to the hypothalamic–pituitary–somatotropic axis (Barabutis 2020b). * Nektarios Barabutis [email protected] 1
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA
2
Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA
3
Divisions of Medical Oncology and Endocrinology, Department of Medicine and Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA
GHRH possesses growth factor activities in cancers, since the activation of the GHRH receptor by this neuropeptide induces cancer promotion and metastasis; both in vivo and in vitro (Barabutis 2020a). The silencing of the intrinsic GHRH expression in human lung, prostate and breast cancers strongly suppresses their proliferation (Barabutis and Schally 2008). GHRH antagonists block the effects
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