Effect of high glucose on vasculature.

To the Editor: Cosentino et al1 report that high glucose causes PKCdependent upregulation of inducible cyclooxygenase and endothelial NO synthase (eNOS) expression in human aortic endothelial cells associated with a selective increase of thromboxane production and reduced NO release. As stated by the authors, these data are in contrast with recent observations that eNOS activity was reduced to 43% in hyperglycemic and/or diabetic aortic cell culture compared with controls.2 High production of NO resulting from increased inducible NO synthase (iNOS) expression may be linked to increased cardiovascular disease in nondiabetic patients.3 Recently, we reported that high glucose4 increased iNOS expression and NO release in working rat hearts. Upregulation of iNOS and raised NO generation were accompanied by a marked concomitant increase of superoxide production. The interaction of superoxide with NO is very rapid and leads to inactivation of NO and production of the potent oxidant peroxynitrite.5 As nitrotyrosine is considered a good marker of peroxynitrite formation,5 detection of nitrotyrosine in hearts perfused with high glucose is strongly suggestive for increased generation of peroxynitrite, which can mediate the toxic effects of high glucose on the heart, as suggested by the detection of cell apoptosis.4 On the other hand, we failed to observe modification of the intensity of eNOS expression in the presence of high glucose.4 Further studies are needed to evaluate whether upregulation of iNOS by high glucose plays a role in the mediation of its toxic effect on the vasculature.