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      Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT

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          Abstract

          Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite. Ghrelin endocrine activities are entirely dependent on its acylation and are mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein–coupled receptor mostly expressed in the pituitary and hypothalamus, previously identified as the receptor for a group of synthetic molecules featuring GH secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its function is currently unknown. Ghrelin, which is expressed in heart, albeit at a much lower level than in the stomach, also exerts a cardio protective effect through an unknown mechanism, independent of GH release. Here we show that both ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2 cardiomyocytes and endothelial cells in vitro through activation of extracellular signal–regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des-acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes, which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des-acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt.

          These findings provide the first evidence that, independent of its acylation, ghrelin gene product may act as a survival factor directly on the cardiovascular system through binding to a novel, yet to be identified receptor, which is distinct from GHSR-1a.

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          Most cited references 34

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          A receptor in pituitary and hypothalamus that functions in growth hormone release.

          Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.
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            The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans.

            Ghrelin is a novel growth hormone-releasing peptide, originally identified in the rat stomach as the endogenous ligand for the growth hormone secretagogue-receptor (GHS-R1a). Ghrelin is involved in the regulation of GH release, but it has recently been suggested that ghrelin may have other actions, including effects on appetite, carbohydrate metabolism, heart, kidney, pancreas, gonads, and cell proliferation. The distribution of ghrelin, its functional receptor (type 1a) and the unspliced, non-functional GHS-R type 1b mRNA expression was investigated in various human tissues using classical and real-time reverse transcription and polymerase chain reaction. GHS-R1a was predominantly expressed in the pituitary and at much lower levels in the thyroid gland, pancreas, spleen, myocardium and adrenal gland. In contrast, ghrelin was found in the stomach, other parts of the gut and, indeed, in all the tissues studied (adrenal gland, atrium, breast, buccal mucosa, esophagus, Fallopian tube, fat tissue, gall bladder, human lymphocytes, ileum, kidney, left colon, liver, lung, lymph node, muscle, muscle, myocardium, ovary, pancreas, pituitary, placenta, prostate, right colon, skin, spleen, testis, thyroid, and vein). GHS-R1b expression was also widespread in all tissues studied. The significance of the widespread tissue distribution of ghrelin remains to be determined. These data suggest that ghrelin might have widespread physiological effects via different, partly unidentified, subtypes of the GHS-R in endocrine and non-endocrine tissues.
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              Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.

              Ghrelin, a novel peptide purified from stomach, is the endogenous ligand for the growth hormone secretagogue receptor and has potent growth hormone-releasing activity. The Ser3 residue of ghrelin is modified by n-octanoic acid, a modification necessary for hormonal activity. We established two ghrelin-specific radioimmunoassays; one recognizes the octanoyl-modified portion and another the C-terminal portion of ghrelin. Using these radioimmunoassay systems, we found that two major molecular forms exist-ghrelin and des-n-octanoyl ghrelin. While ghrelin activates growth-hormone secretagogue (GHS) receptor-expressing cells, the nonmodified des-n-octanyl form of ghrelin, designated as des-acyl ghrelin, does not. In addition to these findings, our radioimmunoassay systems also revealed high concentrations of ghrelin in the stomach and small intestine.
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                Author and article information

                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                23 December 2002
                : 159
                : 6
                : 1029-1037
                Affiliations
                [1 ]Department of Medical Sciences and Interdisciplinary Research Center on Autoimmune Diseases, University Amedeo Avogadro of Piemonte Orientale, Novara 28100, Italy
                [2 ]Department of Anatomy, Pharmacology and Forensic Medicine
                [3 ]Department of Traumatology, Orthopedics and Occupational Health
                [4 ]Department of Human and Animal Biology, Biology, and Biochemistry, University of Torino, 10100 Torino, Italy
                [5 ]Department of Internal Medicine, Biology, and Biochemistry, University of Torino, 10100 Torino, Italy
                [6 ]Department of Biomedical Sciences and Oncology, Biology, and Biochemistry, University of Torino, 10100 Torino, Italy
                [7 ]Department of Genetics, Biology, and Biochemistry, University of Torino, 10100 Torino, Italy
                [8 ]Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, 40530 Göteborg, Sweden
                [9 ]Europeptides, 95100 Argenteuil, France
                Author notes

                Address correspondence to Andrea Graziani, Dept. of Medical Sciences, University Amedeo Avogadro of Piemonte Orientale, v. Solaroli 17, 28100 Novara, Italy. Tel.: 39-0321-660608. Fax: 39-0321-620421. E-mail: graziani@ 123456med.unipmn.it

                Article
                200207165
                10.1083/jcb.200207165
                2173981
                12486113
                Copyright © 2002, The Rockefeller University Press
                Categories
                Article

                Cell biology

                ghrelin; apoptosis; heart; erks; akt

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