doi: 10.1161/01.CIR.0000089098.82604.46
(Circulation. 2003;108:e74.)
© 2003 American Heart Association, Inc.
Correspondence |
Effect of High Glucose on Vasculature
Department of Geriatrics and Metabolic Diseases, Second University of Naples, Italy, raffaele.marfella@unina2.it
To the Editor:
Cosentino et al1 report that high glucose causes PKC-dependent 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.
References
1. Cosentino F, Eto M, De Paolis P, et al. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation. 2003; 107: 1017–1023.
2. Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification of the Akt site. J Clin Invest. 2001; 108: 1341–1348.[CrossRef][Medline] [Order article via Infotrieve]
3. Haywood GA, Tsao PS, von der Leyen HE, et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation. 1996; 93: 1087–1094.
4. Ceriello A, Quagliaro L, D’Amico M, et al. Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes. 2002; 51: 1076–1082.
5. Ischiropoulos H. Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys. 1998; 356: 1–11.[CrossRef][Medline] [Order article via Infotrieve]
Response
Cardiovascular Research, Institute of Physiology, University of Zurich and Cardiovascular Center, University Hospital, Zurich, Switzerland
Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, IRCCS Neuromed, Pozzilli, Italy
Faculty of Biology, University of Konstanz, Germany
We thank Dr. Marfella et al for their letter related to our recent work.1 As we reported, in spite of a paradoxical upregulation of endothelial NO synthase (eNOS), NO release was reduced, and coincubation with antioxidants restored the balance between NO and reactive oxygen species formation. These findings are in agreement with the results of a study performed in an in vivo model of diabetes.2 Although in our study we did not investigate the effect of high glucose on NO synthase activity, we are aware that an impairment of eNOS activity under hyperglycemic conditions could also contribute to reduce NO levels.3 However, we can rule out that decreases in eNOS gene expression contribute to endothelial dysfunction. At both the RNA and the protein levels, the enzyme is upregulated 2- to 3-fold in human aortic endothelial cells (HAECs) exposed to high glucose1 and in vessels from diabetic animals.2
On the basis of these observations, it is reasonable to hypothesize that the superoxide formed may either overwhelm the NO production of the upregulated eNOS or that the eNOS itself may be uncoupled, thereby contributing to superoxide production. Because there is no evidence of expression of inducible NO synthase (iNOS) messenger RNA in HAECs under normal and inflammatory conditions,4 the upregulation of iNOS by high glucose observed in working rat heart5 may not be easily transferred to our experimental setting. However, it is very likely that in the vasculature, the uncoupling of eNOS is associated with induction of iNOS and concomitant increments in NO and superoxide, which may contribute to the formation of high concentration of peroxynitrite in diabetes mellitus.
References
1. Cosentino F, Eto M, De Paolis P, et al. High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation. 2003; 107: 1017–1023.
2. Hink U, Li H, Mollnau H. Mechanisms of endothelial dysfunction in diabetes mellitus. Circ Res. 2001; 88: e14–e22.
3. Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification of the Akt site. J Clin Invest. 2001; 108: 1341–1348.[CrossRef][Medline] [Order article via Infotrieve]
4. MacNaul KL, Hutchinson NI. Differential expression of iNOS and cNOS mRNA in human vascular smooth muscle and endothelial cells under normal and inflammatory conditions. Biochem Biophys Res Commun. 1993; 196: 1330–1334.[CrossRef][Medline] [Order article via Infotrieve]
5. Ceriello A, Quagliaro L, D’Amico M, et al. Acute hyperglycemia induces nitrotyrosine formation and apoptosis in perfused heart from rat. Diabetes. 2002; 51: 1076–1082.
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