High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: Role of protein kinase C and reactive oxygen species

Francesco Cosentino, Masato Eto, Paola De Paolis, Bernd V. Van der Loo, Markus Bachschmid, Volker Ullrich, Alexei Kouroedov, Chiara Delli Gatti, Hana Joch, Massimo Volpe, Thomas F. Lüscher

Research output: Contribution to journalArticlepeer-review

Abstract

Background - Prostaglandins generated by cyclooxygenase (COX) have been implicated in hyperglycemia-induced endothelial dysfunction. However, the role of individual COX isoenzymes as well as the molecular mechanisms linking oxidative stress and endothelial dysfunction in diabetes remains to be clarified. Methods and Results - Human aortic endothelial cells were exposed to normal (5.5 mmol/L) and high (22.2 mmol/L) glucose. Glucose selectively increased mRNA and protein expression of COX-2. Its upregulation was associated with an increase of thromboxane A 2 and a reduction of prostacyclin (PGI 2) release. Glucose-induced activation of PKC resulted in the formation of peroxynitrite and tyrosine nitration of PGI 2 synthase. NO release was reduced despite 2-fold increase of endothelial NO synthase expression. Phorbol ester caused an increase of COX-2 and endothelial NO synthase expression similar to that elicited by glucose. These effects were prevented by the PKC inhibitor calphostin C. N-acetylcysteine, vitamin C, and calphostin C prevented ROS formation, restored NO release, and reduced colocalization of nitrotyrosine and PGI 2 synthase. Expression of p22 phox, a subunit of NAD(P)H oxidase, was increased, and diphenyleneiodonium inhibited ROS formation. By contrast, indomethacin did not affect glucose-induced ROS generation. Conclusions - Thus, high glucose, via PKC signaling, induces oxidative stress and upregulation of COX-2, resulting in reduced NO availability and altered prostanoid profile.

Original languageEnglish
Pages (from-to)1017-1023
Number of pages7
JournalCirculation
Volume107
Issue number7
DOIs
Publication statusPublished - Feb 25 2003

Keywords

  • Diabetes mellitus
  • Nitric oxide
  • Stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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