Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels

Moazed, Banafsheh; Quest, Dale; Gopalakrishnan, Venkat

doi:10.1016/j.ejphar.2008.10.032

Cited by 27 publications

(30 citation statements)

References 40 publications

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“…They reported that DAG evokes endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels. However, this vasodilator response in the perfused rat mesenteric vascular bed was not mediated by the classical GHSR1a (29).…”

Section: The First Indicationsmentioning

confidence: 81%

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MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

Delhanty

Neggers

Lely

2012

European Journal of Endocrinology

212

180

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Des-acyl ghrelin (DAG) is one of the three preproghrelin gene-encoded peptides. Compared with ghrelin and obestatin, it has not received the attention it deserves. DAG has long been considered an inert degradation product of acyl ghrelin (AG). Recent evidence, however, indicates that DAG behaves like a separate hormone. DAG can act together with AG, can antagonize AG, and seems to have AG-independent effects. Therefore, it is believed that DAG must activate its own receptor and that it may also interact with AG at this receptor. Of potential clinical importance is that an increasing number of studies suggest that DAG might be a functional inhibitor of ghrelin and that DAG can suppress ghrelin levels in humans. Therefore, DAG or DAG analogs might be good candidates for future treatment of metabolic disorders or other conditions in which antagonism of AG actions could be beneficial, such as diabetes, obesity, and Prader-Willi syndrome.

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Section: The First Indicationsmentioning

confidence: 81%

“…Interestingly, the PP-releasing effect of AG, but not obestatin, was counteracted by coadministration of DAG. Apparently, AG and obestatin inhibit spontaneous PP secretion at physiologically Fat mass in rodents (29,30) Insulin sensitivity and postprandial…”

Section: The First Indicationsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

Delhanty

Neggers

Lely

2012

European Journal of Endocrinology

212

180

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“…Other mechanisms have also been hypothesized to play a role in mediating the effects of ghrelin. In the intestinal vascular bed, both peptides were shown to promote vasodilatation by a mechanism not involving GHSR-1a activation (16). Moreover, endothelial calcium-activated potassium channels (17), MAPK, and Akt (18) were found to be involved in the vascular and apoptotic effects of des acyl ghrelin.…”

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confidence: 99%

Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

Grossini¹,

Raina²,

Farruggio³

et al. 2016

Endocrinology

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Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P Ͻ .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n ϭ 5) or ␣-and ␤-adrenoceptors (n ϭ 5 each) did not abolish the observed responses, NO synthase inhibition (n ϭ 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells. (Endocrinology 157: 2403-2415, 2016) T he ghrelin-related peptides, acylated ghrelin and desacylated ghrelin, are gastrointestinal hormones that have been reported to exert variable effects on the cardiovascular system. Apart from being able to stimulate food intake and adiposity (1-4), ghrelin has been found to reduce arterial and pulmonary blood pressure (BP) (5-8), to increase myocardial contractility (5, 9), and to exert opposite effects on different vascular beds (10 -13). For example, ghrelin has been shown to increase human forearm blood flow and dilate human mammary and rat mesenteric arteries, whereas in rats and pigs, it caused coronary vasoconstriction.The deacylated form of ghrelin, des-acyl ghrelin, is far more abundant in circulation than ghrelin and is devoid of any endocrine activity (1, 2, 4, 14), although several authors strongly suggest that des-acyl ghrelin has intrinsic and specific actions in many physiological and pathophysiological conditions, mainly as a functional antagonist of ghrelin (15). To date, however, the function of des-acyl ghrelin is currently unknown, with the few studies exam- Abbreviations: BP, blood pressure; CEC, coronary artery endothelial cell; DAG, des-acyl ghrelin; dP/dt max , maximum rate of change of LV systolic pressure; eNOS, endothelial NO synthase; GHSR, GH secretagogue receptor; LAD, left anterior descending coronary artery; L-NAME, N-nitro-L arginine methyl ester; LV, left ventricular; NO, nitric oxide; NOS, NO synthase; PKA, protein kinase A; PLC, phospholipase C; PO 2...

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“…Neither coagulation step was affected by ghrelin or its derivatives, even at levels higher than physiological levels. (Bednarek et al 2000, Holst et al 2005, Moazed et al 2009), whereas these peptides did not show any obvious effects on blood coagulation or platelet activation (Fig. 8B).…”

Section: Figurementioning

confidence: 91%

“…because of its ability to complete reactions (Bednarek et al 2000, Moazed et al 2009, and the lipid modification is required for binding to GHSR1a. Ghrelin exhibits orexigenic and endocrine actions owing to both central and peripheral mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Identification of activated protein C as a ghrelin endopeptidase in bovine plasma

Satou¹,

Nishi²,

Hishinuma³

et al. 2014

Journal of Endocrinology

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Ghrelin is a natural GH secretagogue first identified in the stomach. The ghrelin peptide is 28 amino acids long with an octanoic acid attached to Ser 3 near the N-terminus. This lipid modification is essential for the interaction between ghrelin and the ghrelin-specific receptor GH secretagogue receptor type 1a (GHSR1a), whereas the five or more residues of the N-terminus seem to be sufficient to activate GHSR1a to the same level as those of full-length ghrelin. In this study, we found that ghrelin was converted into smaller fragments during incubation with animal plasma in vitro and in a mouse model. Mass spectrometric analysis revealed that both acyl and desacyl ghrelin were hydrolyzed at the peptide bond between Arg 15 and Lys 16 , generating an N-terminal peptide consisting of the first 15 residues. Next, we partially purified a ghrelin endopeptidase from bovine plasma and identified the enzyme as an anticoagulant serine protease-activated protein C. Octanoyl-truncated ghrelin(1-15) activated GHSR1a-dependent signaling similar to the full-length peptide, as assayed using the cell-based early-growth factor 1 reporter system. Moreover, administration of the protein C-activating agent, ProTac, to mice enhanced the production of octanoyl ghrelin(1-15) in circulation. These results indicate that ghrelin is processed into shorter peptides in circulation under thrombotic and inflammatory conditions, although high doses of the short-form or full-length ghrelin did not have any obvious effects on thromboplastin time or platelet aggregation in human plasma. Truncation of ghrelin might be responsible for altering structural characteristics such as stability, hydrophobicity, and affinity with circulating macromolecules.

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Des-acyl ghrelin fragments evoke endothelium-dependent vasodilatation of rat mesenteric vascular bed via activation of potassium channels

Cited by 27 publications

References 40 publications

MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

Identification of activated protein C as a ghrelin endopeptidase in bovine plasma

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