Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT.
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.
Baldanzi
Gianluca
G
Department of Medical Sciences and Interdisciplinary Research Center on Autoimmune Diseases, University Amedeo Avogadro of Piemonte Orientale, Novara 28100, Italy.
Filigheddu
Nicoletta
N
Cutrupi
Santina
S
Catapano
Filomena
F
Bonissoni
Sara
S
Fubini
Alberto
A
Malan
Daniela
D
Baj
Germano
G
Granata
Riccarda
R
Broglio
Fabio
F
Papotti
Mauro
M
Surico
Nicola
N
Bussolino
Federico
F
Isgaard
Jorgen
J
Deghenghi
Romano
R
Sinigaglia
Fabiola
F
Prat
Maria
M
Muccioli
Giampiero
G
Ghigo
Ezio
E
Graziani
Andrea
A
D000818:Animals; D017209:Apoptosis; D001667:Binding, Competitive; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D002469:Cell Separation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D054439:Ghrelin; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008858:Microscopy, Phase-Contrast; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D009842:Oligopeptides / Q000494:pharmacology; D036361:Peptide Hormones / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013141:Spiro Compounds / Q000494:pharmacology; D013552:Swine; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D016895:Culture Media, Serum-Free; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D054439:Ghrelin; D007211:Indoles; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009842:Oligopeptides; D036361:Peptide Hormones; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013141:Spiro Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; C422650:ghrelin, des-n-octanoyl; C086184:hexarelin; C494920:Akt1 protein, rat; C022616:thiazolyl blue; C094817:ibutamoren mesylate