Unacylated Ghrelin Rescues Endothelial Progenitor Cell Function in Individuals with Type 2 Diabetes

Overview

Journal Diabetes

Specialty Endocrinology

Date 2010 Jan 14

PMID 20068135

Citations 29

Authors

Gabriele Togliatto

Antonella Trombetta

Patrizia Dentelli

Alessandra Baragli

Arturo Rosso

Riccarda Granata

Dario Ghigo

Luigi Pegoraro

Ezio Ghigo

Maria Felice Brizzi

Affiliations

Soon will be listed here.

Abstract

Objective: Acylated ghrelin (AG) is a diabetogenic and orexigenic gastric polypeptide. These properties are not shared by the most abundant circulating form, which is unacylated (UAG). An altered UAG/AG profile together with an impairment of circulating endothelial progenitor cell (EPC) bioavailability were found in diabetes. Based on previous evidence for the beneficial cardiovascular effects of AG and UAG, we investigated their potential to revert diabetes-associated defects.

Research Design And Methods: Healthy human subjects, individuals with type 2 diabetes, and ob/ob mice were AG or UAG infused. EPC mobilization in patients and mice was evaluated, and the underlying molecular mechanisms were investigated in bone marrow stromal cells. Recovered EPCs were also evaluated for the activity of senescence regulatory pathways and for NADPH oxidase activation by knocking down p47(phox) and Rac1. Finally, UAG modulation of human EPC vasculogenic potential was investigated in an in vivo mouse model.

Results: Neither AG nor UAG had any effect in healthy subjects. However, systemic administration of UAG, but not AG, prevented diabetes-induced EPC damage by modulating the NADPH oxidase regulatory protein Rac1 and improved the vasculogenic potential both in individuals with type 2 diabetes and in ob/ob mice. In addition, unlike AG, UAG facilitated the recovery of bone marrow EPC mobilization. Crucial to EPC mobilization by UAG was the rescue of endothelial NO synthase (eNOS) phosphorylation by Akt, as UAG treatment was ineffective in eNOS knockout mice. Consistently, EPCs expressed specific UAG-binding sites, not recognized by AG.

Conclusions: These data provide the rationale for clinical applications of UAG in pathologic settings where AG fails.

Citing Articles

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders.

Fritz E, Singewald N, De Bundel D Front Synaptic Neurosci. 2020; 12:594484.

PMID: 33192444 PMC: 7652849. DOI: 10.3389/fnsyn.2020.594484.

Heal the heart through gut (hormone) ghrelin: a potential player to combat heart failure.

Gupta S, Mitra A Heart Fail Rev. 2020; 26(2):417-435.

PMID: 33025414 DOI: 10.1007/s10741-020-10032-2.

Unacylated Ghrelin Improves Vascular Dysfunction and Attenuates Atherosclerosis during High-Fat Diet Consumption in Rodents.

Zanetti M, Gortan Cappellari G, Graziani A, Barazzoni R Int J Mol Sci. 2019; 20(3).

PMID: 30682769 PMC: 6387360. DOI: 10.3390/ijms20030499.

Unacylated ghrelin prevents mitochondrial dysfunction in a model of ischemia/reperfusion liver injury.

Rossetti A, Togliatto G, Rolo A, Teodoro J, Granata R, Ghigo E Cell Death Discov. 2018; 3:17077.

PMID: 29354291 PMC: 5712633. DOI: 10.1038/cddiscovery.2017.77.

Ghrelin, MicroRNAs, and Critical Limb Ischemia: Hungering for a Novel Treatment Option.

Neale J, Pearson J, Katare R, Schwenke D Front Endocrinol (Lausanne). 2018; 8:350.

PMID: 29326658 PMC: 5733488. DOI: 10.3389/fendo.2017.00350.

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