on July 8, 2002
Circulation. 2002
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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Submitted on March 5, 2002
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. * To whom correspondence should be addressed. 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.
Revised on May 8, 2002
Accepted on May 9, 2002
Insulin-Dependent Activation of Endothelial Nitric Oxide Synthase Is Impaired by O-Linked Glycosylation Modification of Signaling Proteins in Human Coronary Endothelial Cells
Massimo Federici MD*,
Key words: atherosclerosis • diabetes mellitus • endothelium • insulin • metalloproteinases
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|
|
|
|
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|
|
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