(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
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Abstract |
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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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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The relation between diabetes and premature vascular disease is well established.1 2 One of the defects involves endothelial dysfunction characterized by impaired endothelium-dependent responses.3 4 In isolated blood vessels, exposure to elevated glucose causes endothelial dysfunction.5 6 However, the molecular mechanisms of hyperglycemia-induced endothelial dysfunction remain unknown. The endothelium acts as a transducer of humoral signals and physical forces. Many signals modify eNOS activity and NO release. Human eNOS has been cloned.7 The promoter region of the human eNOS gene contains tentative regulatory sequences, including phorbol esters, cAMP, and acute-phase, shear stress, and sterol-responsive elements.8 Exercise,9 mechanical stimuli,10 11 and sex hormones12 13 increase eNOS mRNA and protein, whereas tumor necrosis factor-
decreases eNOS mRNA
posttranscriptionally.14 This suggests that
arterial tone is modulated by changes in expression of eNOS
and NO production. Because little is known about the effects of
hyperglycemia on the NO pathway, we studied the effect of an elevated
concentration of glucose on eNOS mRNA and protein expression and
production of NO and superoxide anion
(O2-) in cultured human aortic
endothelial cells. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cell Culture
Human aortic endothelial cells were obtained from Clonetics. Cells were first grown to confluence in humidified air (5% CO2 at 37°C). Then control (5.5 mmol/L) or elevated glucose concentrations (22.2 mmol/L) were administered for 5 days with concomitant lowering of serum concentration in the medium to 2% to keep the cells in the quiescent state. Cells up to passage 6 were used.
Amplification of eNOS mRNA by RT-PCR
The relative expression of eNOS mRNA in control and
high-glucose–treated endothelial cells was evaluated
by RT-PCR. Cellular RNA was reverse transcribed and first-strand cDNA
was used as a template in PCR. cDNA aliquots were amplified with
primers specific for eNOS and housekeeping gene
glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) in a Perkin-Elmer GeneAmp 9600 cycler.
Western Blot
eNOS protein was analyzed by Western blot using an
anti-human eNOS antibody (Transduction Laboratories) as previously
described.13
Measurement of NO
We evaluated NO production by measuring levels of
nitrite (NO2-), the oxidized product of
NO, by Griess reaction as previously described.13 15
Briefly, basal and ionomycin-stimulated production were
measured by subtracting NO2- values at time 0
from cumulative concentrations obtained after 3 hours' incubation and
60 minutes' exposure to ionomycin (1 µmol/L), respectively.
Measurement of O2-
Production of O2- was
measured as the superoxide dismutase–inhibitable reduction of
cytochrome c, as previously described.16 17
Statistical Analysis
Results are expressed as mean±SEM; n indicates number of
experiments. Statistical evaluation of the data was performed by use of
unpaired Student's t test and ANOVA followed by Fisher's
test. A value of P<.05 was considered statistically
significant.
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Results |
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Effect of Glucose on eNOS mRNA and Protein Expression
The exposure to a high level of glucose (22.2 mmol/L) for 5 days significantly increased the expression of eNOS mRNA compared with control (5.5 mmol/L; Fig 1
). By contrast, the
expression of GAPDH mRNA did not change in
endothelial cells exposed to high levels of glucose
(PCR product: 8.6±1.8 and 10±1.8 ng for control and
high-glucose–treated cells, respectively; n=9). When control and
high-glucose–treated cells were compared, expression of eNOS, as
detected by Western blotting, was also greater in cells exposed to high
glucose. Densitometric analysis showed an almost twofold
increase in eNOS protein expression (Fig 1). However, when
endothelial cells were exposed to a similar
concentration of mannitol, eNOS protein expression was not affected
(OD: 100±17 and 108±20 arbitrary units for control and
mannitol-treated cells, respectively; n=3).
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Effect of Glucose on NO and O2-
Production
Both basal and stimulated NO2-
production by ionomycin (1 µmol/L) were increased in
endothelial cells exposed to high levels of glucose
(Fig 2). The stimulatory effect of ionomycin was
inhibited by L-NMMA (5x10-4 mol/L, 410±33
and 63±15 pmol per well per hour in the absence and in the presence of
L-NMMA, respectively; n=4). However, O2-
production was more than 300% higher in high-glucose–treated
cells (Fig 2).
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Discussion |
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This study demonstrates for the first time that in human aortic endothelial cells, prolonged exposure to high glucose concentrations increases eNOS gene expression, protein expression, NO2- release, and production of O2-. Diabetes is an important cardiovascular risk factor and is associated with impaired endothelium-dependent relaxations. Hence, we would have expected glucose-induced downregulation of the eNOS gene. However, eNOS mRNA and protein expression were approximately twofold higher in endothelial cells exposed to elevated glucose. Accordingly, NO production, which we assessed by measuring changes in NO2- levels, was increased by 40%. However, the production of O2- was increased more than 300% in high-glucose–treated cells. The interaction of O2- with NO is very rapid and leads to inactivation of NO and production of the potent oxidant peroxynitrite.18 19 This may contribute to impaired endothelial function by stimulating arachidonic acid metabolism, lipid peroxidation, and prostanoid production.20 21 In isolated arteries, prolonged exposure to elevated glucose concentrations impairs endothelium-dependent relaxations.5 6 Hyperglycemia-induced endothelial dysfunction may result from decreased production of NO, inactivation of NO by oxygen-derived free radicals, or increased production of contracting factors.22 Our results clearly indicate that the synthesis and release of NO are not diminished after exposure to high concentrations of glucose. On the contrary, basal and ionomycin-induced production of NO2- were increased in high-glucose–treated cells. Selective upregulation of eNOS mRNA and protein expression together with the inhibitory effect of L-NMMA on NO2- production are consistent with this conclusion.
Superoxide anions are attractive candidates as mediators of endothelial dysfunction in diabetes.23 In agreement with our results, O2- formation is involved in glucose-induced changes of endothelial Ca2+/endothelium-derived relaxing factor signaling.24 Indeed, superoxide dismutase, a scavenger of O2-, prevents the impaired endothelium-dependent relaxations caused by elevated glucose.25 In diabetic arteries, O2- may produce contractile effects not only by inactivation of NO but also via formation of hydrogen peroxide and hydroxyl radical, which stimulate the production of contractile prostanoids.23 24 25 26 Our findings support the hypothesis of an increased NO inactivation by O2- as an important mechanism for the impairment of endothelium-dependent relaxations in arteries exposed to high levels of glucose. The mechanisms by which high glucose levels simultaneously increase eNOS expression and production of O2- are not known. The experiments with mannitol certainly rule out an effect of osmolarity. One potential mechanism is the synthesis of diacylglycerol and protein kinase C activation.27 Indeed, protein kinase C is chronically activated in diabetic tissues.28 The promoter region of the human eNOS gene contains a phorbol ester–responsive element.8 In normal blood vessels, activation of protein kinase C by phorbol esters reduces endothelium-dependent relaxations as in diabetes.6 Hence, the release of O2- and prostaglandins by protein kinase C may explain the impaired endothelium-dependent relaxations.29
An increased production of O2- may also occur via auto-oxidation of glucose and/or nonenzymatic protein glycation.30 Further studies are needed to elucidate the signal-transduction pathway involved.
In summary, this study demonstrates that elevated concentrations of glucose increase eNOS gene and protein expression as well as NO release. However, upregulation of eNOS and increased NO release are associated with a marked concomitant increase of O2- production. These findings may explain the impaired endothelial function and be important in the development of diabetic vascular disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by the Swiss National Research Foundation grant 32-35541.91 (Dr Lüscher), National Heart, Lung, and Blood Institute grant HL-535427 (Dr Katusic), and the Mayo Foundation (Dr Katusic). Dr Cosentino was supported by a grant from Bristol-Myers Squibb, Italy, for cardiovascular research.
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Footnotes |
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Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10-13, 1996, and previously published in abstract form (Circulation. 1996;94 [suppl I]:I-1093).
Received March 26, 1997; revision received May 8, 1997; accepted May 13, 1997.
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S. Cai, J. Khoo, and K. M. Channon Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells Cardiovasc Res, March 1, 2005; 65(4): 823 - 831. [Abstract] [Full Text] [PDF]
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 A. B. El-Remessy, M. Bartoli, D. H. Platt, D. Fulton, and R. B. Caldwell Oxidative stress inactivates VEGF survival signaling in retinal endothelial cells via PI 3-kinase tyrosine nitration J. Cell Sci., January 1, 2005; 118(1): 243 - 252. [Abstract] [Full Text] [PDF]
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 B. F. Schrijvers, A. S. De Vriese, and A. Flyvbjerg From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines Endocr. Rev., December 1, 2004; 25(6): 971 - 1010. [Abstract] [Full Text] [PDF]
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H. Kinoshita, T. Azma, K. Nakahata, H. Iranami, Y. Kimoto, M. Dojo, O. Yuge, and Y. Hatano Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K+ Channels in Human Omental Artery Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2290 - 2295. [Abstract] [Full Text] [PDF]
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P. N. Chander, O. Gealekman, S. V. Brodsky, S. Elitok, A. Tojo, M. Crabtree, S. S. Gross, and M. S. Goligorsky Nephropathy in Zucker Diabetic Fat Rat Is Associated with Oxidative and Nitrosative Stress: Prevention by Chronic Therapy with a Peroxynitrite Scavenger Ebselen J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2391 - 2403. [Abstract] [Full Text] [PDF]
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A. Kouroedov, M. Eto, H. Joch, M. Volpe, T. F. Luscher, and F. Cosentino Selective Inhibition of Protein Kinase C{beta}2 Prevents Acute Effects of High Glucose on Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells Circulation, July 6, 2004; 110(1): 91 - 96. [Abstract] [Full Text] [PDF]
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T. Janatuinen, J. Knuuti, J. O. Toikka, M. Ahotupa, P. Nuutila, T. Ronnemaa, and O. T. Raitakari Effect of Pravastatin on Low-Density Lipoprotein Oxidation and Myocardial Perfusion in Young Adults With Type 1 Diabetes Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1303 - 1308. [Abstract] [Full Text] [PDF]
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T. Kobayashi, T. Matsumoto, K. Ooishi, and K. Kamata Differential expression of {alpha}2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H135 - H148. [Abstract] [Full Text] [PDF]
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 F Violi, L Loffredo, L Musella, and A Marcoccia Should antioxidant status be considered in interventional trials with antioxidants? Heart, June 1, 2004; 90(6): 598 - 602. [Abstract] [Full Text] [PDF]
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F. R. DeRubertis, P. A. Craven, M. F. Melhem, and E. M. Salah Attenuation of Renal Injury in db/db Mice Overexpressing Superoxide Dismutase: Evidence for Reduced Superoxide-Nitric Oxide Interaction Diabetes, March 1, 2004; 53(3): 762 - 768. [Abstract] [Full Text] [PDF]
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N. J. Alp and K. M. Channon Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 413 - 420. [Abstract] [Full Text]
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M. Raitakari, T. Ilvonen, M. Ahotupa, T. Lehtimaki, A. Harmoinen, P. Suominen, J. Elo, J. Hartiala, and O. T. Raitakari Weight Reduction With Very-Low-Caloric Diet and Endothelial Function in Overweight Adults: Role of Plasma Glucose Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 124 - 128. [Abstract] [Full Text] [PDF]
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M. W. Brands, T. D. Bell, and B. Gibson Nitric Oxide May Prevent Hypertension Early in Diabetes by Counteracting Renal Actions of Superoxide Hypertension, January 1, 2004; 43(1): 57 - 63. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, J. F. Keaney Jr., and M. A. Creager Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2392 - H2398. [Abstract] [Full Text] [PDF]
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M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I Circulation, September 23, 2003; 108(12): 1527 - 1532. [Full Text] [PDF]
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N. G. Abraham, T. Kushida, J. McClung, M. Weiss, S. Quan, R. Lafaro, Z. Darzynkiewicz, and M. Wolin Heme Oxygenase-1 Attenuates Glucose-Mediated Cell Growth Arrest and Apoptosis in Human Microvessel Endothelial Cells Circ. Res., September 19, 2003; 93(6): 507 - 514. [Abstract] [Full Text] [PDF]
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N. Ihlemann, C. Rask-Madsen, A. Perner, H. Dominguez, T. Hermann, L. Kober, and C. Torp-Pedersen Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H875 - H882. [Abstract] [Full Text] [PDF]
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 A. B. El-Remessy, G. Abou-Mohamed, R. W. Caldwell, and R. B. Caldwell High Glucose-Induced Tyrosine Nitration in Endothelial Cells: Role of eNOS Uncoupling and Aldose Reductase Activation Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 3135 - 3143. [Abstract] [Full Text] [PDF]
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R. Komers and S. Anderson Paradoxes of nitric oxide in the diabetic kidney Am J Physiol Renal Physiol, June 1, 2003; 284(6): F1121 - F1137. [Abstract] [Full Text] [PDF]
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 A. B. El-Remessy, M. A. Behzadian, G. Abou-Mohamed, T. Franklin, R. W. Caldwell, and R. B. Caldwell Experimental Diabetes Causes Breakdown of the Blood-Retina Barrier by a Mechanism Involving Tyrosine Nitration and Increases in Expression of Vascular Endothelial Growth Factor and Urokinase Plasminogen Activator Receptor Am. J. Pathol., June 1, 2003; 162(6): 1995 - 2004. [Abstract] [Full Text] [PDF]
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 I. P. Salt, V. A. Morrow, F. M. Brandie, J. M. C. Connell, and J. R. Petrie High Glucose Inhibits Insulin-stimulated Nitric Oxide Production without Reducing Endothelial Nitric-oxide Synthase Ser1177 Phosphorylation in Human Aortic Endothelial Cells J. Biol. Chem., May 23, 2003; 278(21): 18791 - 18797. [Abstract] [Full Text] [PDF]
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A. Ceriello New Insights on Oxidative Stress and Diabetic Complications May Lead to a "Causal" Antioxidant Therapy Diabetes Care, May 1, 2003; 26(5): 1589 - 1596. [Abstract] [Full Text] [PDF]
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E. R. Gross, J. F. LaDisa Jr., D. Weihrauch, L. E. Olson, T. T. Kress, D. A. Hettrick, P. S. Pagel, D. C. Warltier, and J. R. Kersten Reactive oxygen species modulate coronary wall shear stress and endothelial function during hyperglycemia Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1552 - H1559. [Abstract] [Full Text] [PDF]
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F. Kimura, G. Hasegawa, H. Obayashi, T. Adachi, H. Hara, M. Ohta, M. Fukui, Y. Kitagawa, H. Park, N. Nakamura, et al. Serum Extracellular Superoxide Dismutase in Patients With Type 2 Diabetes: Relationship to the development of micro- and macrovascular complications Diabetes Care, April 1, 2003; 26(4): 1246 - 1250. [Abstract] [Full Text] [PDF]
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F. Cosentino, M. Eto, P. De Paolis, B. van der Loo, M. Bachschmid, V. Ullrich, A. Kouroedov, C. Delli Gatti, H. Joch, M. Volpe, 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, February 25, 2003; 107(7): 1017 - 1023. [Abstract] [Full Text] [PDF]
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The ENCORE Investigators* Effect of Nifedipine and Cerivastatin on Coronary Endothelial Function in Patients With Coronary Artery Disease: The ENCORE I Study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function) Circulation, January 28, 2003; 107(3): 422 - 428. [Abstract] [Full Text] [PDF]
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C. Flores, S. Rojas, C. Aguayo, J. Parodi, G. Mann, J. D. Pearson, P. Casanello, and L. Sobrevia Rapid Stimulation of L-Arginine Transport by D-Glucose Involves p42/44mapk and Nitric Oxide in Human Umbilical Vein Endothelium Circ. Res., January 10, 2003; 92(1): 64 - 72. [Abstract] [Full Text] [PDF]
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 G. E. Mann, D. L. Yudilevich, and L. Sobrevia Regulation of Amino Acid and Glucose Transporters in Endothelial and Smooth Muscle Cells Physiol Rev, January 1, 2003; 83(1): 183 - 252. [Abstract] [Full Text] [PDF]
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 Z. He, C. Rask-Madsen, and G.L. King Mechanisms of cardiovascular complications in diabetes and potential new pharmacological therapies Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B51 - B57. [Abstract] [PDF]
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 V Peponis, M Papathanasiou, A Kapranou, C Magkou, A Tyligada, A Melidonis, T Drosos, and N M Sitaras Protective role of oral antioxidant supplementation in ocular surface of diabetic patients Br J Ophthalmol, December 1, 2002; 86(12): 1369 - 1373. [Abstract] [Full Text] [PDF]
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C. Szabo, A. Zanchi, K. Komjati, P. Pacher, A. S. Krolewski, W. C. Quist, F. W. LoGerfo, E. S. Horton, and A. Veves Poly(ADP-Ribose) Polymerase Is Activated in Subjects at Risk of Developing Type 2 Diabetes and Is Associated With Impaired Vascular Reactivity Circulation, November 19, 2002; 106(21): 2680 - 2686. [Abstract] [Full Text] [PDF]
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 A. N. Friedman, C. Ritter, J. C. F. Moreira, F. Dal-Pizzol, M. G. Ziegler, X. Bao, R. Matz, Y. Higashi, K. Chayama, and M. Yoshizumi Renovascular Hypertension, Endothelial Function, and Oxidative Stress N. Engl. J. Med., November 7, 2002; 347(19): 1528 - 1530. [Full Text] [PDF]
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R. Nagai, Y. Unno, M. C. Hayashi, S. Masuda, F. Hayase, N. Kinae, and S. Horiuchi Peroxynitrite Induces Formation of N{varepsilon}-(Carboxymethyl)Lysine by the Cleavage of Amadori Product and Generation of Glucosone and Glyoxal From Glucose: Novel Pathways for Protein Modification by Peroxynitrite Diabetes, September 1, 2002; 51(9): 2833 - 2839. [Abstract] [Full Text] [PDF]
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K. Y. Lin, A. Ito, T. Asagami, P. S. Tsao, S. Adimoolam, M. Kimoto, H. Tsuji, G. M. Reaven, and J. P. Cooke Impaired Nitric Oxide Synthase Pathway in Diabetes Mellitus: Role of Asymmetric Dimethylarginine and Dimethylarginine Dimethylaminohydrolase Circulation, August 20, 2002; 106(8): 987 - 992. [Abstract] [Full Text] [PDF]
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 R. Maas, E. Schwedhelm, J. Albsmeier, and R. H Boger The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function Vascular Medicine, August 1, 2002; 7(3): 213 - 225. [Abstract] [PDF]
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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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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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G. R. Drummond, H. Cai, M. E. Davis, S. Ramasamy, and D. G. Harrison Transcriptional and Posttranscriptional Regulation of Endothelial Nitric Oxide Synthase Expression by Hydrogen Peroxide Circ. Res., February 18, 2000; 86(3): 347 - 354. [Abstract] [Full Text] [PDF]
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