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

• 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 beta-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.

Nyckelord

1-Phosphatidylinositol 3-Kinase

metabolism

Adenylate Cyclase

metabolism

Adrenergic beta-Agonists

pharmacology

Animals

Apoptosis

drug effects

Calcium

metabolism

Caspase 3

metabolism

Cell Line

Cell Survival

Cyclic AMP

metabolism

Cyclic AMP-Dependent Protein Kinases

metabolism

Cytoprotection

Growth Hormone-Releasing Hormone

analogs & derivatives

metabolism

pharmacology

Isoproterenol

pharmacology

Mitogen-Activated Protein Kinase 1

metabolism

Mitogen-Activated Protein Kinase 3

metabolism

Myocardial Contraction

drug effects

Myocardial Reperfusion Injury

metabolism

pathology

prevention & control

Myocytes

Cardiac

drug effects

enzymology

metabolism

pathology

Perfusion

RNA

Messenger

metabolism

Rats

Receptors

Neuropeptide

antagonists & inhibitors

metabolism

Receptors

Pituitary Hormone-Regulating Hormone

antagonists & inhibitors

metabolism

Recovery of Function

Signal Transduction

drug effects

genetics

Time Factors

Ventricular Function

Le

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