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Diabetes 52:2795-2804, 2003
© 2003 by the American Diabetes Association, Inc.

Intermittent High Glucose Enhances Apoptosis Related to Oxidative Stress in Human Umbilical Vein Endothelial Cells

The Role of Protein Kinase C and NAD(P)H-Oxidase Activation

Lisa Quagliaro1, Ludovica Piconi1, Roberta Assaloni2, Lucia Martinelli2, Enrico Motz2, and Antonio Ceriello2

1 Morpurgo-Hofman Research Laboratory on Aging, Udine, Italy
2 Department of Pathology and Medicine, Experimental and Clinical, University of Udine, Udine, Italy

The effects of intermittent and constant high glucose in the formation of nitrotyrosine and 8-hydroxydeoxyguanosine (markers of oxidative stress), as well as the possible linkage between oxidative stress and apoptosis in endothelial cells, have been evaluated. Stable high glucose increased nitrotyrosine, 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis levels. However, these effects were more pronounced in intermittent high glucose. Protein kinase C (PKC) was elevated in both such conditions, particularly in intermittent glucose. The adding of the PKC inhibitors bisindolylmaleimide-I and LY379196, a specific inhibitor of PKC-ß isoforms, normalized nitrotyrosine and reduced 8-OHdG concentration and cell apoptosis in both stable and intermittent high glucose. Similar results were obtained with the MnSOD mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride that normalized nitrotyrosine, 8-OHdG, and apoptosis and inhibited PKC activation. NAD(P)H oxidase was also measured. NAD(P)H oxidase components p47phox, p67phox, and p22phox was overexpressed during both stable and intermittent high glucose. PKC inhibition and MnSOD mimetic normalized this phenomenon. In conclusion, our study shows that the exposure of endothelial cells to both stable and intermittent high glucose stimulates reactive oxygen species overproduction also through PKC-dependent activation of NAD(P)H oxidase, leading to increased cellular apoptosis. Our data suggest that glucose fluctuations may also be involved in the development of vascular injury in diabetes.

Address correspondence and reprint requests to Prof. Antonio Ceriello, Department of Internal Medicine, University of Udine, P.le S. Maria della Misericordia, 33100 Udine, Italy. E-mail: Antonio.Ceriello{at}Dpmsc.uniud.it


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