Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes.
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.


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.
Togliatto
Gabriele
G
Department of Internal Medicine, University of Torino, Torino, Italy.
Trombetta
Antonella
A
Dentelli
Patrizia
P
Baragli
Alessandra
A
Rosso
Arturo
A
Granata
Riccarda
R
Ghigo
Dario
D
Pegoraro
Luigi
L
Ghigo
Ezio
E
Brizzi
Maria Felice
MF
D000215:Acylation; D000368:Aged; D000818:Animals; D001782:Blood Donors; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D054439:Ghrelin / Q000627:therapeutic use*; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D012016:Reference Values; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*
D054439:Ghrelin; D008055:Lipids