Hexarelin Protects H9c2 Cardiomyocytes from Doxorubicin-Induced Cell Death

Filigheddu, Nicoletta; Fubini, A; Baldanzi, Gianluca; Cutrupi, Santina; Ghè, Corrado; Catapano, Filomena; Broglio, Fabio; Bosìa, Amalia; Papotti, Mauro; Muccioli, Giampiero; Ghigo, Ezio; Deghenghi, Romano; Graziani, Andrea

doi:10.1385/endo:14:1:113

Cited by 39 publications

(33 citation statements)

References 20 publications

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“…In particular, peptidyl GHS, such as hexarelin, improve the post-ischemic recovery of hearts from either aged or GH-deficient rats Müller et al, 2002) and increase left ventricular ejection in patients with severe GH deficiency (Bisi et al, 1999;Imazio et al, 2002). An antiapoptotic action of synthetic GHS has also been shown on H9c2 cardiomyocytes (Filigheddu et al, 2001). Moreover, we have previously reported that the peptidyl GHS hexarelin has negative inotropic effect on rat papillary muscle (Bedendi et al, 2001).…”

Section: Discussionmentioning

confidence: 80%

“…In particular, peptidyl GHS, such as hexarelin, improve the post-ischemic recovery of hearts of either aged or GH-deficient rats and increase left ventricular ejection in patients with severe GH-deficiency (Bisi et al, 1999;Imazio et al, 2002). A stimulatory effect on cell proliferation (Pettersson et al, 2002) and an antiapoptotic action (Filigheddu et al, 2001) of GHS on the cardiomyocyte cell line H9c2 have also been shown. The natural ligand of the GHS type 1a receptor has more recently been discovered as a gastric-derived hormone named ghrelin (Kojima et al, 1999).…”

Section: Introductionmentioning

confidence: 96%

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Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Bedendi

Alloatti

Marcantoni

et al. 2003

European Journal of Pharmacology

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169

116

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The mechanisms underlying the cardiac activities of synthetic growth hormone secretagogues (GHS) are still unclear. The natural ligand of the GHS receptors, i.e. ghrelin, classically binds the GHS receptor and exerts endocrine actions in acylated forms only; its cardiovascular actions still need to be investigated further. In order to clarify these aspects, we studied the effects of either the synthetic peptidyl GHS hexarelin (1 AM), or the natural ghrelin (50 nM) and the endogenous ghrelin derivatives des-Gln 14 -ghrelin (1 -100 nM) and des-octanoyl ghrelin (50 nM), on the tension developed by guinea pig papillary muscle and on L-type Ca 2 + current (I Ca ) of isolated ventricular cells. The binding of these molecules to ventricular cell membrane homogenates was also studied. We observed that all peptides reduced the tension developed at low frequencies (60 -120 beats/min) in a dose-dependent manner. No alteration in cardiac contractility was induced by desGln 14 -ghrelin or des-octanoylated ghrelin when the endocardial endothelium had been removed or after cyclooxygenase blockade. Pretreatment with tyramine (2 AM) had no effect on the inotropic response induced by des-Gln 14 -ghrelin. No significant effect on I Ca of isolated ventricular cells was observed in the presence of des-Gln 14 -ghrelin (100 nM). The order of potency on the tension of papillary muscle was: des-octanoyl ghrelin>ghrelin = des-Gln 14 -ghrelin>hexarelin. This gradient of potency was consistent with the binding experiments performed on ventricular membranes where either acylated or unacylated ghrelin forms, and hexarelin, recognized a common high-affinity binding site. In conclusion, ghrelin, des-Gln 14 -ghrelin and des-octanoyl ghrelin, show similar negative inotropic effect on papillary muscle; as des-octanoyl ghrelin is peculiarly devoid of any GH-releasing activity, the cardiotropic action of these molecules is independent of GH release. The binding studies and the experiments performed both on the isolated cells and on papillary muscle after endothelium removal or cyclooxygenase blockade indicate that the cardiotropic action of natural and synthetic ghrelin analogues reflects the interaction with a novel GHS receptor (peculiarly common for ghrelin and des-octanoyl ghrelin), leading to release of cyclooxygenase metabolites from endothelial cells, as indicated by direct measurement of prostacyclin metabolite 6-keto-PGF 1a .

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 96%

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Bedendi

Alloatti

Marcantoni

et al. 2003

European Journal of Pharmacology

Self Cite

169

116

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“…Papotti et al (2000) have also shown specific binding to human cardiac tissue using iodinated Tyr-Ala-hexarelin. Binding of hexarelin to H9c2 cells has previously been shown (Filigheddu et al 2001); however, to the best of our knowledge no studies demonstrating direct effects of GHS and also binding of ghrelin to cardiomyocytes have yet been published.…”

Section: Introductionmentioning

confidence: 92%

Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation

Pettersson

Muccioli²,

Granata³

et al. 2002

Journal of Endocrinology

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Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 µM (147 3% of control, P<0·01) and elicited maximal effects at concentrations around 30 µM. This activity was seen already after 12 h of incubation with a maximal effect after 18 h (176 9% of control, P<0·01). Ghrelin also had a significant stimulatory effect on thymidine incorporation (129 2% of control at 3 µM and 18 h, P<0·05). The stimulatory effect on thymidine incorporation of hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin was specific and no stimulatory effect was observed with the truncated GH-releasing peptide EP51389 or the non-peptidyl GHS MK-0677. In competitive binding studies, 125 I-labeled Tyr-Alahexarelin was used as radioligand and competition curves showed displacement with hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin, whereas MK-0677 and EP51389 produced very little displacement at 1 µM concentration, adding further support for an alternative subtype binding site in the heart compared with the pituitary. In conclusion, we have demonstrated a dose-dependent and specific stimulation of cardiomyocyte thymidine incorporation by natural and synthetic GHS analogues, suggesting increased cell proliferation and binding of GHS to H9c2 cardiomyocyte cell membranes. These findings support potential peripheral effects of GHS on the cardiovascular system independent of an increased GH secretion.

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“…139,140 Ghrelin and GHSs inhibit cell proliferation in thyroid tumor cells 140,141 and breast cancer cells. 138 Nonacylated ghrelin also exerts antiproliferative actions. 139 Because unacylated ghrelin is unable to bind to the GHS-R 1a, these data suggest that the antiproliferative effects of acylated and unacylated ghrelin on cancer cells are mediated via a GHS-R subtype that is different from GHS-R 1a.…”

Section: Antiproliferative Effectsmentioning

confidence: 99%

“…138 Because unacylated ghrelin does not activate the GHS-R 1a, 54 these data indicate that another subtype of GHS-R exists in cardiac tissue and that unacylated ghrelin has some biological activity. 81 Thus, long-term administration of ghrelin may become a treatment strategy for patients with heart failure.…”

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confidence: 97%

Ghrelin, an endogenous growth hormone secretagogue with diverse endocrine and nonendocrine effects

Bhatti¹,

Ham²,

Mol³

et al. 2006

American Journal of Veterinary Research

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Hexarelin Protects H9c2 Cardiomyocytes from Doxorubicin-Induced Cell Death

Cited by 39 publications

References 20 publications

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation

Ghrelin, an endogenous growth hormone secretagogue with diverse endocrine and nonendocrine effects

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