Aim: The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH), stimulates growth hormone 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 signaling mechanisms. Methods and results: RT-PCR analysis showed GHRH-receptor 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 signaling. Isoproterenol strongly up-regulated the mRNA and protein of the proapoptotic inducible cAMP early repressor (ICER), whereas GHRH completely blocked this effect. Similarly to ARVMs, in H9c2 cardiac cells GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signaling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischemia-reperfusion injury. These effects involved PI3K/Akt signaling and were inhibited by JV-1-36. Conclusions: Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signaling mechanisms and protects against ischemia/reperfusion injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.
Ghrh promotes survival of cardiac myocytes in vitro and protects against ischemia-reperfusion injury in rat heart
GRANATA, Riccarda;SETTANNI, Fabio;TROVATO, Letizia;GALLO, Maria Pia;DESTEFANIS, SILVIA;SCARLATTI, FRANCESCA;BRERO, Alessia;RAMELLA, Roberta;VOLANTE, Marco;LEVI, Renzo;PAPOTTI, Mauro Giulio;ALLOATTI, Giuseppe;GHIGO, Ezio
2009-01-01
Abstract
Aim: The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH), stimulates growth hormone 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 signaling mechanisms. Methods and results: RT-PCR analysis showed GHRH-receptor 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 signaling. Isoproterenol strongly up-regulated the mRNA and protein of the proapoptotic inducible cAMP early repressor (ICER), whereas GHRH completely blocked this effect. Similarly to ARVMs, in H9c2 cardiac cells GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signaling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischemia-reperfusion injury. These effects involved PI3K/Akt signaling and were inhibited by JV-1-36. Conclusions: Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signaling mechanisms and protects against ischemia/reperfusion injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
