Background-Hyperglycemia impairs functional properties of cytosolic and nuclear proteins via O-linked glycosylation modification (O-GlcNAcylation). We studied the effects of O-GlcNAcylation on insulin signaling in human coronary artery endothelial cells. Methods and Results-O-GlcNAcylation impaired the metabolic branch of insulin signaling, ie, insulin receptor (IR) activation of the IR substrate (IRS)/phosphatidylinositol 3-kinase (PI3-K)/Akt, whereas it enhanced the rnitogenic branch, ie. ERK-1/2 and p38 (mitogen-activated protein kinase). Both in vivo and in vitro phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt were reduced by hyperglycemia and hexosamine activation. Insulin-induced CNOS activity in vivo was reduced by hyperglycemia and hexosamine activation. which was coupled to increased activation and expression of matrix metalloproteinase-2 and -9: these phenomena were reversed by inhibition of the hexosamine pathway. Finally, carotid plaques from type 2 diabetic patients showed increased endothelial O-GlcNAcylation with respect to nondiabetics. Conclusions-Our data show that hyperglycemia, through the hexosamine pathway, impairs activation of the IR/IRS/PI3-K/Akt pathway, resulting in deregulation of eNOS activity.
Federici, M., Menghini, R., Mauriello, A., Hribal, M.L., Ferrelli, F., Lauro, D., et al. (2002). Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. CIRCULATION, 106(4), 466-472.
Tipologia: | Articolo su rivista |
Citazione: | Federici, M., Menghini, R., Mauriello, A., Hribal, M.L., Ferrelli, F., Lauro, D., et al. (2002). Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. CIRCULATION, 106(4), 466-472. |
Lingua: | English |
Settore Scientifico Disciplinare: | Settore M-EDF/01 - Metodi e Didattiche delle Attivita' Motorie Settore MED/09 - Medicina Interna |
Revisione (peer review): | Sì, ma tipo non specificato |
Tipo: | Articolo |
Rilevanza: | Rilevanza internazionale |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1161/01.CIR.0000023043.02648.51 |
Stato di pubblicazione: | Pubblicato |
Data di pubblicazione: | 2002 |
Titolo: | Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells |
Autori: | |
Autori: | Federici, M; Menghini, R; Mauriello, A; Hribal, ML; Ferrelli, F; Lauro, D; Sbraccia, P; Spagnoli, LG; Sesti, G; Lauro, R |
Appare nelle tipologie: | 01 - Articolo su rivista |