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

Pettersson, Ingvar; Muccioli, Giampiero; Granata, Riccarda; Deghenghi, Romano; Ghigo, Ezio; Ohlsson, Claes; Isgaard, Jörgen

doi:10.1677/joe.0.1750201

Cited by 98 publications

(65 citation statements)

References 56 publications

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“…This pattern of expression is in agreement with the proposed role for ghrelin in the autocrine/paracrine control of cell proliferation and cancer. Proliferative actions of ghrelin (or its synthetic analogs, the GHSs) are observed in prostate (PC-3) and thyroid (anaplastic carcinoma; ARO) cancer cell lines as well as the cardiomyocyte H9c2 cell line and cultured adrenocortical cells , Pettersson et al 2002, Andreis et al 2003, Jeffery et al 2003. Conversely, anti-proliferative effects of ghrelin/GHSs are observed in several thyroid (papillary carcinoma; NPA, follicular carcinoma; WRO), lung (CALU-1), and breast (MCF7, T47D, MDA-MB231) cancer cell lines , Ghe et al 2002 as well as in immature Leydig cells of the testis .…”

Section: Human Datamentioning

confidence: 99%

Role of ghrelin in reproduction

García

López²,

Álvarez³

et al. 2007

Reproduction

107

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Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as a pleiotropic modulator of diverse biological functions, including energy homeostasis and, lately reproduction. Here, we review recent reports evaluating the reproductive effects and sites of action of ghrelin, with particular emphasis regarding its role as a molecule integrating reproductive function and energy status. Data gleaned from rodent studies clearly show that besides having direct gonadal effects, ghrelin may participate in the regulation of gonadotropin secretion and it may influence the timing of puberty. In addition, experimental data showing that ghrelin and/or its receptor are expressed in normal human ovary and testis as well as in human ovarian and testicular tumors raise the possibility that the ghrelin system may be involved in the control of cell proliferation in these tumors. We propose that ghrelin either acting as an endocrine and/or paracrine signal may play a major role in the endocrine network that integrates energy balance and reproduction.

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Section: Human Datamentioning

confidence: 99%

Role of ghrelin in reproduction

García

López²,

Álvarez³

et al. 2007

Reproduction

107

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“…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%

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

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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“…At the functional level, n-octanoylated ghrelin treatment increases the rate of proliferation in a number of cell lines, including human prostate cancer (Jeffery et al 2002), HepG2 hepatoma (Murata et al 2002) and pancreatic adenocarcinoma cancer cell lines (Duxbury et al 2003), rodent pituitary tumour cells (Nanzer et al 2004), as well as some normal cell lines and primary cell cultures (Pettersson et al 2002, Andreis et al 2003, Kim et al 2004, Mazzocchi et al 2004, Zhang et al 2004b, Maccarinelli et al 2005. There is evidence to suggest that a similar system could exist in female hormone-dependent cancers, such as breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines

Jeffery

Murray²,

Yeh³

et al. 2005

Endocr Relat Cancer

111

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While oestrogen, progesterone and growth factors, including growth hormone (GH), are clearly implicated in the pathogenesis of breast cancer, there is now evidence that the newly described ghrelin axis is also involved. The aims of this study were to investigate the expression of the ghrelin axis in breast cancer tissues and cell lines and to examine the effect of ghrelin on breast cancer cell proliferation in vitro. Ghrelin and its functional receptor, the growth hormone secretagogue receptor (GHSR) type 1a, were expressed in normal breast tissue and breast cancer specimens and cell lines. In contrast, the truncated GHSR type 1b isoform was exclusively expressed in breast carcinoma, suggesting that it has potential as a diagnostic marker. Ghrelin treatment significantly increases the proliferation of the MDA-MB-435 and MDA-MB-231 breast cancer cell lines in vitro. In addition, we have described the expression of a human preproghrelin isoform, exon 3-deleted preproghrelin, which encodes mature ghrelin plus a novel C-terminal peptide. Quantitative RT-PCR was used to demonstrate that this mRNA isoform is highly expressed in the MDA-MB-435 metastatic breast cancer cell line relative to the benign MCF-10A breast epithelial cell line. The unique C-terminal peptide of exon 3-deleted preproghrelin is expressed in the glandular epithelium of breast cancer tissues, with high-grade carcinoma exhibiting the strongest immunoreactivity. The data presented here suggest that components of the ghrelin axis may represent novel markers for breast cancer and potential therapeutic targets.

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

Cited by 98 publications

References 56 publications

Role of ghrelin in reproduction

Role of ghrelin in reproduction

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

Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines

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