Cardiovascular Research Advance Access first published online on March 17, 2009
This version [Corrected Proof] published online on April 2, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp090
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Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia–reperfusion injury in rat heart
1 Laboratory of Molecular and Cellular Endocrinology, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy
2 Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy
3 Department of Animal and Human Biology, University of Turin, Turin, Italy
4 Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy
5 Department of Internal Medicine, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden
* Corresponding author. Tel: +39 011 633 55 32; fax: +39 011 664 74 21. E-mail address: riccarda.granata{at}unito.it.
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.
KEYWORDS GHRH; Cardioprotection; Cardiac myocyte cell death; Ischaemia/reperfusion injury
Time for primary review: 22 days
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