Journal
CIRCULATION
Volume 106, Issue 4, Pages 466-472Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.0000023043.02648.51
Keywords
atherosclerosis; diabetes mellitus; endothelium; insulin; metalloproteinases
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available