Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 17, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp090
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GHRH promotes survival of cardiac myocytes in vitro and protects against ischemia-reperfusion injury in rat heart
1 Laboratory of Molecular and Cellular Endocrinology
2 Division of Endocrinology and Metabolism, Department of Internal Medicine
3 Department of Animal and Human Biology
4 Department of Clinical and Biological Sciences and San Luigi Hospital, University of Turin, Turin, Italy
5 Department of Internal Medicine, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
Address all correspondence and requests for reprints to: Riccarda Granata, PhD, Laboratory of Molecular and Cellular Endocrinology, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti 14 - 10126 Turin, Italy, E-mail: riccarda.granata{at}unito.it, Phone: (+39) 011 633 55 32, Fax: (+39) 011 664 74 21
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.
KEYWORDS GHRH; cardioprotection; cardiac myocyte cell death; ischemia/reperfusion injury
Time for primary review: 22 days
Abbreviations: AC, adenylyl cyclase; ARVMs, adult rat ventricular myocytes; cAMP, CREB, cAMP response element-binding protein; ERK, extracellular signal-regulated kinase; GHRH, growth hormone-releasing hormone; GHRH-R, GHRH receptor; ICER, inducible cAMP early represso
MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide-3 kinase; PKA, protein kinase A; siRNA, small interference RNA; SVs, splice variants.
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