(Circulation. 1997;96:25-28.)
© 1997 American Heart Association, Inc.
Articles |
High Glucose Increases Nitric Oxide Synthase Expression and Superoxide Anion Generation in Human Aortic Endothelial Cells
From the Departments of Cardiology and Cardiovascular Research, University Hospitals, Bern and Zürich, Switzerland, and Departments of Anesthesiology and Pharmacology (Z.S.K.), Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Thomas F. Lüscher, MD, FACC, FESC, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail100771.1237{at}compuserve.com
Background Hyperglycemia is a primary cause of premature vascular disease. Endothelial cell dysfunction characterized by diminished endothelium-dependent relaxations is likely to be involved. Little is known about the molecular mechanisms of hyperglycemia-induced endothelial dysfunction.
Methods and Results This study was designed to determine the effect of hyperglycemia on the L-arginine/nitric oxide (NO) pathway. Expression of endothelial nitric oxide synthase (eNOS) mRNA and production of NO were studied in human aortic endothelial cells exposed to control levels (5.5 mmol/L) and high levels (22.2 mmol/L) of glucose for 5 days. We examined the effect of glucose on NO release by measuring changes in nitrite (NO2-) levels by Griess reaction. Superoxide anion (O2-) production was also examined by the ferrocytochrome c assay. NOS mRNA and protein expression, which were evaluated by reverse transcription–polymerase chain reaction and Western blotting, were approximately twofold greater in endothelial cells exposed to high glucose. Elevated glucose levels increased NO2- production by only 40% but increased the release of O2- by more than threefold.
Conclusions The present study demonstrates that prolonged exposure to high glucose increases eNOS gene expression, protein expression, and NO release. However, upregulation of eNOS and NO release is associated with a marked concomitant increase of O2- production. These results provide the molecular basis for understanding how chronic exposure to elevated glucose leads to an imbalance between NO and O2-. This may explain impaired endothelial function and be important for diabetic vascular disease.
Key Words: diabetes mellitus • endothelium-derived factors • free radicals
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A. Ceriello, L. Quagliaro, B. Catone, R. Pascon, M. Piazzola, B. Bais, G. Marra, L. Tonutti, C. Taboga, and E. Motz Role of Hyperglycemia in Nitrotyrosine Postprandial Generation Diabetes Care, August 1, 2002; 25(8): 1439 - 1443. [Abstract] [Full Text] [PDF]
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M. Christ, J. Bauersachs, C. Liebetrau, M. Heck, A. Gunther, and M. Wehling Glucose Increases Endothelial-Dependent Superoxide Formation in Coronary Arteries by NAD(P)H Oxidase Activation: Attenuation by the 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Atorvastatin Diabetes, August 1, 2002; 51(8): 2648 - 2652. [Abstract] [Full Text] [PDF]
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M. C. Lansang and N. K. Hollenberg Renal Perfusion and the Renal Hemodynamic Response to Blocking the Renin System in Diabetes: Are the Forces Leading to Vasodilation and Vasoconstriction Linked? Diabetes, July 1, 2002; 51(7): 2025 - 2028. [Abstract] [Full Text] [PDF]
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R. W. van Etten, E. J.P. de Koning, M. L. Honing, E. S. Stroes, C. A. Gaillard, and T. J. Rabelink Intensive Lipid Lowering by Statin Therapy Does Not Improve Vasoreactivity in Patients With Type 2 Diabetes Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 799 - 804. [Abstract] [Full Text] [PDF]
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A. Ceriello, L. Quagliaro, M. D'Amico, C. Di Filippo, R. Marfella, F. Nappo, L. Berrino, F. Rossi, and D. Giugliano Acute Hyperglycemia Induces Nitrotyrosine Formation and Apoptosis in Perfused Heart From Rat Diabetes, April 1, 2002; 51(4): 1076 - 1082. [Abstract] [Full Text] [PDF]
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M.-C. Desco, M. Asensi, R. Marquez, J. Martinez-Valls, M. Vento, F. V. Pallardo, J. Sastre, and J. Vina Xanthine Oxidase Is Involved in Free Radical Production in Type 1 Diabetes: Protection by Allopurinol Diabetes, April 1, 2002; 51(4): 1118 - 1124. [Abstract] [Full Text] [PDF]
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B. Schnyder, M. Pittet, J. Durand, and S. Schnyder-Candrian Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E87 - E94. [Abstract] [Full Text] [PDF]
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M.-H. Zou, C. Shi, and R. A. Cohen High Glucose via Peroxynitrite Causes Tyrosine Nitration and Inactivation of Prostacyclin Synthase That Is Associated With Thromboxane/Prostaglandin H2 Receptor-Mediated Apoptosis and Adhesion Molecule Expression in Cultured Human Aortic Endothelial Cells Diabetes, January 1, 2002; 51(1): 198 - 203. [Abstract] [Full Text] [PDF]
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B. M. Matata and M. Galinanes Effect of Diabetes on Nitric Oxide Metabolism During Cardiac Surgery Diabetes, November 1, 2001; 50(11): 2603 - 2610. [Abstract] [Full Text] [PDF]
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A. J. Cayatte, A. Rupin, J. Oliver-Krasinski, K. Maitland, P. Sansilvestri-Morel, M.-F. Boussard, M. Wierzbicki, T. J. Verbeuren, and R. A. Cohen S17834, a New Inhibitor of Cell Adhesion and Atherosclerosis That Targets NADPH Oxidase Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1577 - 1584. [Abstract] [Full Text] [PDF]
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K. A. EARLE, S. MEHROTRA, R. N. DALTON, E. DENVER, and R. SWAMINATHAN Defective Nitric Oxide Production and Functional Renal Reserve in Patients with Type 2 Diabetes Who Have Microalbuminuria of African and Asian Compared with White Origin J. Am. Soc. Nephrol., October 1, 2001; 12(10): 2125 - 2130. [Abstract] [Full Text] [PDF]
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P. A. Craven, M. F. Melhem, S. L. Phillips, and F. R. DeRubertis Overexpression of Cu2+/Zn2+ Superoxide Dismutase Protects Against Early Diabetic Glomerular Injury in Transgenic Mice Diabetes, September 1, 2001; 50(9): 2114 - 2125. [Abstract] [Full Text] [PDF]
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 W. Wang, S. Wang, E. V. Nishanian, A. Del Pilar Cintron, R. A. Wesley, and R. L. Danner Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway Am J Physiol Cell Physiol, August 1, 2001; 281(2): C544 - C554. [Abstract] [Full Text] [PDF]
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L. Haegeli, K. Quitzau, T.F. Luscher, and Steering Committee and the Investigators of the EN From endothelial dysfunction to clinical events Concept and update on the ENCORE trials Eur. Heart J. Suppl., May 1, 2001; 3(suppl_B): B12 - B19. [Abstract] [PDF]
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J. A. Beckman, A. B. Goldfine, M. B. Gordon, and M. A. Creager Ascorbate Restores Endothelium-Dependent Vasodilation Impaired by Acute Hyperglycemia in Humans Circulation, March 27, 2001; 103(12): 1618 - 1623. [Abstract] [Full Text] [PDF]
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S. V. Brodsky, A. M. Morrishow, N. Dharia, S. S. Gross, and M. S. Goligorsky Glucose scavenging of nitric oxide Am J Physiol Renal Physiol, March 1, 2001; 280(3): F480 - F486. [Abstract] [Full Text] [PDF]
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U. Hink, H. Li, H. Mollnau, M. Oelze, E. Matheis, M. Hartmann, M. Skatchkov, F. Thaiss, R. A. K. Stahl, A. Warnholtz, et al. Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus Circ. Res., February 2, 2001; 88 (2): e14 - e22. [Abstract] [Full Text] [PDF]
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 N. P. Andrews, A. Prasad, and A. A. Quyyumi N-acetylcysteine improves coronary and peripheral vascular function J. Am. Coll. Cardiol., January 1, 2001; 37(1): 117 - 123. [Abstract] [Full Text] [PDF]
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C. Kimura, M. Oike, T. Koyama, and Y. Ito Impairment of endothelial nitric oxide production by acute glucose overload Am J Physiol Endocrinol Metab, January 1, 2001; 280(1): E171 - E178. [Abstract] [Full Text] [PDF]
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 V. P Montecinos, C. Aguayo, C. Flores, A. W Wyatt, J. D Pearson, G. E Mann, and L. Sobrevia Regulation of adenosine transport by D-glucose in human fetal endothelial cells: involvement of nitric oxide, protein kinase C and mitogen-activated protein kinase J. Physiol., December 15, 2000; 529(3): 777 - 790. [Abstract] [Full Text] [PDF]
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L. M. Title, P. M. Cummings, K. Giddens, and B. A. Nassar Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2185 - 2191. [Abstract] [Full Text] [PDF]
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S. M. Fitzgerald and M. W. Brands Nitric oxide may be required to prevent hypertension at the onset of diabetes Am J Physiol Endocrinol Metab, October 1, 2000; 279(4): E762 - E768. [Abstract] [Full Text] [PDF]
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R. Komers, J. N. Lindsley, T. T. Oyama, K. M. Allison, and S. Anderson Role of neuronal nitric oxide synthase (NOS1) in the pathogenesis of renal hemodynamic changes in diabetes Am J Physiol Renal Physiol, September 1, 2000; 279(3): F573 - F583. [Abstract] [Full Text] [PDF]
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C. K. Roberts, N. D. Vaziri, X. Q. Wang, and R. J. Barnard Enhanced NO Inactivation and Hypertension Induced by a High-Fat, Refined-Carbohydrate Diet Hypertension, September 1, 2000; 36(3): 423 - 429. [Abstract] [Full Text] [PDF]
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M. J. Mullen, D. Wright, A. E. Donald, S. Thorne, H. Thomson, and J. E. Deanfield Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study J. Am. Coll. Cardiol., August 1, 2000; 36(2): 410 - 416. [Abstract] [Full Text] [PDF]
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K. M. Channon, H. Qian, and S. E. George Nitric Oxide Synthase in Atherosclerosis and Vascular Injury : Insights From Experimental Gene Therapy Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 1873 - 1881. [Abstract] [Full Text] [PDF]
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 B. M. Matata and M. Galinanes Cardiopulmonary bypass exacerbates oxidative stress but does not increase proinflammatory cytokine release in patients with diabetes compared with patients without diabetesRegulatory effects of exogenous nitric oxide J. Thorac. Cardiovasc. Surg., July 1, 2000; 120(1): 1 - 11. [Abstract] [Full Text] [PDF]
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Y. Ding, N. D. Vaziri, R. Coulson, V. S. Kamanna, and D. D. Roh Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E11 - E17. [Abstract] [Full Text] [PDF]
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F. M. Ho, S. H. Liu, C. S. Liau, P. J. Huang, and S. Y. Lin-Shiau High Glucose-Induced Apoptosis in Human Endothelial Cells Is Mediated by Sequential Activations of c-Jun NH2-Terminal Kinase and Caspase-3 Circulation, June 6, 2000; 101(22): 2618 - 2624. [Abstract] [Full Text] [PDF]
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M. Guha, W. Bai, J. L. Nadler, and R. Natarajan Molecular Mechanisms of Tumor Necrosis Factor alpha Gene Expression in Monocytic Cells via Hyperglycemia-induced Oxidant Stress-dependent and -independent Pathways J. Biol. Chem., June 2, 2000; 275(23): 17728 - 17739. [Abstract] [Full Text] [PDF]
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W. Kossenjans, A. Eis, R. Sahay, D. Brockman, and L. Myatt Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1311 - H1319. [Abstract] [Full Text] [PDF]
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