High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells

Francesco Cosentino, Keiichi Hishikawa, Zvonimir S. Katusic, Thomas F. Lüscher

Research output: Contribution to journalArticlepeer-review

652 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)25-28
Number of pages4
Issue number1
StatePublished - Jul 1 1997


  • Diabetes mellitus
  • Endothelium-derived factors
  • Free radicals

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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