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.

Nyckelord

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

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