title: GH-releasing hormone induces cardioprotection in isolated male rat heart via activation of RISK and SAFE pathways.
abstract: GHRH stimulates GH synthesis and release from the pituitary and exerts direct effects in extrapituitary tissues. We have previously shown that pretreatment with GHRH reduces cardiomyocyte apoptosis and improves heart function in isolated rat hearts subjected to ischemia/reperfusion (I/R). Here, we determined whether GHRH given at reperfusion reduces myocardial reperfusion injury and investigated the molecular mechanisms involved in GHRH effects. Isolated rat hearts subjected to I/R were treated at the onset of reperfusion with: 1) GHRH; 2) GHRH+GHRH antagonist JV-1-36; 3) GHRH+mitochondrial ATP-dependent potassium channel inhibitor 5-hydroxydecanoate; 4) GHRH+mitochondrial permeability transition pore opener atractyloside; 5) GHRH+ phosphoinositide 3-kinase/Akt inhibitor Wortmannin (WM); and 6) GHRH+signal transducer and activator of transcription-3 inhibitor tyrphostin-AG490 (AG490). GHRH reduced infarct size at the end of reperfusion and reverted contractility dysfunction in I/R hearts. These effects were inhibited by either JV-1-36, 5-hydroxydecanoate, atractylosid, WM, or AG490. Western blot analysis on left ventricles showed GHRH-induced phosphorylation of either the reperfusion injury salvage kinases (RISK), phosphoinositide 3-kinase/Akt, ERK1/2, and glycogen synthase kinase-3β or signal transducer and activator of transcription-3, as part of the survivor activating factor enhancement (SAFE) pathway. GHRH-induced activation of RISK and SAFE pathways was blocked by JV-1-36, WM, and AG490. Furthermore, GHRH increased the phosphorylation of endothelial nitric oxide synthase and AMP-activated protein kinase and preserved postischemic nicotinamide adenine dinucleotide (NAD(+)) levels. These results suggest that GHRH protects the heart from I/R injury through receptor-mediated mechanisms, leading to activation of RISK and SAFE pathways, which converge on mitochondria and possibly on AMP-activated protein kinase.
authors: Department of Clinical and Biological Sciences, University of Torino, 10126 Torino, Italy.
authors: Claudia
authors: C
authors: Penna
authors: Fabio
authors: F
authors: Settanni
authors: Francesca
authors: F
authors: Tullio
authors: Letizia
authors: L
authors: Trovato
authors: Pasquale
authors: P
authors: Pagliaro
authors: Giuseppe
authors: G
authors: Alloatti
authors: Ezio
authors: E
authors: Ghigo
authors: Riccarda
authors: R
authors: Granata
mesh_terms: D000818:Animals; D013007:Growth Hormone-Releasing Hormone / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D013007:Growth Hormone-Releasing Hormone; D019869:Phosphatidylinositol 3-Kinases; C048250:somatotropin releasing hormone receptor