|Göteborgs universitets publikationer
Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT.
Författare och institution:
Gianluca Baldanzi (-); Nicoletta Filigheddu (-); Santina Cutrupi (-); Filomena Catapano (-); Sara Bonissoni (-); Alberto Fubini (-); Daniela Malan (-); Germano Baj (-); Riccarda Granata (-); Fabio Broglio (-); Mauro Papotti (-); Nicola Surico (-); Federico Bussolino (-); Jörgen Isgaard (Institutionen för invärtesmedicin); Romano Deghenghi (-); Fabiola Sinigaglia (-); Maria Prat (-); Giampiero Muccioli (-); Ezio Ghigo (-); Andrea Graziani (-)
The Journal of cell biology, 159 ( 6 ) s. 1029-37
Artikel, refereegranskad vetenskaplig
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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP
1-Phosphatidylinositol 3-Kinase, metabolism, Animals, Apoptosis, Binding, Competitive, Blotting, Western, Cell Death, drug effects, Cell Separation, Cells, Cultured, Culture Media, Serum-Free, pharmacology, Dose-Response Relationship, Drug, Doxorubicin, pharmacology, Endothelium, Vascular, metabolism, Enzyme Activation, Enzyme Inhibitors, pharmacology, Flow Cytometry, Indoles, pharmacology, Inhibitory Concentration 50, Microscopy, Phase-Contrast, Mitogen-Activated Protein Kinase 1, metabolism, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, metabolism, Myocardium, cytology, Oligopeptides, pharmacology, Peptide Hormones, metabolism, Peptides, metabolism, Protein Binding, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, metabolism, Proto-Oncogene Proteins c-akt, Rats, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Spiro Compounds, pharmacology, Swine, Tetrazolium Salts, pharmacology, Thiazoles, pharmacology, Time Factors