Circulation. 2002;106:466-472
Published online before print July 8, 2002, doi: 10.1161/01.CIR.0000023043.02648.51
Published online before print July 8, 2002, doi: 10.1161/01.CIR.0000023043.02648.51
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(Circulation. 2002;106:466.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Insulin-Dependent Activation of Endothelial Nitric Oxide Synthase Is Impaired by O-Linked Glycosylation Modification of Signaling Proteins in Human Coronary Endothelial Cells
From Department of Internal Medicine (M.F., R.M., F.F., D.L., P.S., R.L.) and Department of Biopathology (A.M., L.G.S.), University of Tor Vergata, Rome, Italy; Department of Medicine (M.L.H.), College of Physicians and Surgeons of Columbia University, New York, NY; and Department of Clinical and Experimental Medicine (G.S.), University of Catanzaro, Catanzaro, Italy.
Correspondence to Massimo Federici, Department of Internal Medicine, University of Rome "Tor Vergata," Via Montpellier 1, 135, 00133 Rome, Italy. E-mail federicm{at}uniroma2.it
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 mitogenic 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 eNOS 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.
Key Words: atherosclerosis • diabetes mellitus • endothelium • insulin • metalloproteinases
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