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Published online 16 December 2002. doi:10.1083/jcb.200207165
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© The Rockefeller University Press, 0021-9525/2002/12/1029 $5.00
The Journal of Cell Biology, Volume 159, Number 6, 1029-1037

Article

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

Gianluca Baldanzi1, Nicoletta Filigheddu1, Santina Cutrupi1, Filomena Catapano2, Sara Bonissoni1, Alberto Fubini3, Daniela Malan4, Germano Baj1, Riccarda Granata5, Fabio Broglio5, Mauro Papotti6, Nicola Surico1, Federico Bussolino7, Jorgen Isgaard8, Romano Deghenghi9, Fabiola Sinigaglia1, Maria Prat1, Giampiero Muccioli2, Ezio Ghigo5 and Andrea Graziani1

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

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{at}med.unipmn.it

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.

Key Words: ghrelin; apoptosis; heart; ERKs; Akt


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