Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia–reperfusion injury in rat heart

• Published in: Cardiovascular research 2009-07, Vol.83 (2), p.303-312
• Main Authors: Granata, Riccarda, Trovato, Letizia, Gallo, Maria Pia, Destefanis, Silvia, Settanni, Fabio, Scarlatti, Francesca, Brero, Alessia, Ramella, Roberta, Volante, Marco, Isgaard, Jorgen, Levi, Renzo, Papotti, Mauro, Alloatti, Giuseppe, Ghigo, Ezio
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-Kinase; Adenylate Cyclase; Adenylyl Cyclases - metabolism; Adrenergic beta-Agonists; Adrenergic beta-Agonists - pharmacology; analogs & derivatives; Animals; antagonists & inhibitors; Apoptosis; Apoptosis - drug effects; Calcium; Calcium - metabolism; Cardiac; Cardiac myocyte cell death; Cardioprotection; Caspase 3; Caspase 3 - metabolism; Cell Line; Cell Survival; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytoprotection; drug effects; enzymology; genetics; GHRH; Growth Hormone-Releasing Hormone; Growth Hormone-Releasing Hormone - analogs & derivatives; Growth Hormone-Releasing Hormone - metabolism; Growth Hormone-Releasing Hormone - pharmacology; Ischaemia/reperfusion injury; Isoproterenol; Isoproterenol - pharmacology; Medical and Health Sciences; Medicin och hälsovetenskap; Messenger; metabolism; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase 3 - metabolism; Myocardial Contraction; Myocardial Contraction - drug effects; Myocardial Reperfusion Injury; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neuropeptide; pathology; Perfusion; pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Pituitary Hormone-Regulating Hormone; prevention & control; Rats; Receptors; Receptors, Neuropeptide - antagonists & inhibitors; Receptors, Neuropeptide - metabolism; Receptors, Pituitary Hormone-Regulating Hormone - antagonists & inhibitors; Receptors, Pituitary Hormone-Regulating Hormone - metabolism; Recovery of Function; RNA; RNA, Messenger - metabolism; Signal Transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Time Factors; Ventricular Function; Ventricular Function, Left - drug effects
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvp090

Aims The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and release in the pituitary. GHRH also exerts proliferative effects in extrapituitary cells, whereas GHRH antagonists have been shown to suppress cancer cell proliferation. We investigated GHRH effects on cardiac myocyte cell survival and the underlying signalling mechanisms. Methods and results Reverse transcriptase–polymerase chain reaction analysis showed GHRH receptor (GHRH-R) mRNA in adult rat ventricular myocytes (ARVMs) and in rat heart H9c2 cells. In ARVMs, GHRH prevented cell death and caspase-3 activation induced by serum starvation and by the β-adrenergic receptor agonist isoproterenol. The GHRH-R antagonist JV-1-36 abolished GHRH survival action under both experimental conditions. GHRH-induced cardiac cell protection required extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide-3 kinase (PI3K)/Akt activation and adenylyl cyclase/cAMP/protein kinase A signalling. Isoproterenol strongly upregulated the mRNA and protein of the pro-apoptotic inducible cAMP early repressor, whereas GHRH completely blocked this effect. Similar to ARVMs, in H9c2 cardiac cells, GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signalling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischaemia–reperfusion (I/R) injury. These effects involved PI3K/Akt signalling and were inhibited by JV-1-36. Conclusion Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signalling mechanisms and protects against I/R injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.