Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction: REVIEW

Csaba Szabo

Research output: Contribution to journalReview articlepeer-review

129 Scopus citations

Abstract

Here we overview the role of reactive nitrogen species (nitrosative stress) and associated pathways in the pathogenesis of diabetic vascular complications. Increased extracellular glucose concentration, a principal feature of diabetes mellitus, induces a dysregulation of reactive oxygen and nitrogen generating pathways. These processes lead to a loss of the vascular endothelium to produce biologically active nitric oxide (NO), which impairs vascular relaxations. Mitochondria play a crucial role in this process: endothelial cells placed in increase extracellular glucose respond with a marked increase in mitochondrial superoxide formation. Superoxide, when combining with NO generated by the endothelial cells (produced by the endothelial isoform of NO synthase), leads to the formation of peroxynitrite, a cytotoxic oxidant. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through a multitude of mechanisms including substrate depletion and uncoupling of endothelial isoform of NO synthase. Another pathomechanism involves DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). PARP-mediated poly(ADP-ribosyl)ation and inhibition of glyceraldehyde-3- phosphate dehydrogenase importantly contributes to the development of diabetic vascular complications: it induces activation of multiple pathways of injury including activation of nuclear factor kappa B, activation of protein kinase C and generation of intracellular advanced glycation end products. Reactive species generation and PARP play key roles in the pathogenesis of 'glucose memory' and in the development of injury in endothelial cells exposed to alternating high/low glucose concentrations.

Original languageEnglish (US)
Pages (from-to)713-727
Number of pages15
JournalBritish Journal of Pharmacology
Volume156
Issue number5
DOIs
StatePublished - Mar 2009
Externally publishedYes

Keywords

  • Cell death
  • DNA
  • Diabetic complications
  • Endothelial dysfunction
  • Mitochondria
  • Nitric oxide
  • Oxidative stress
  • PARP
  • Peroxynitrite
  • Superoxide

ASJC Scopus subject areas

  • Pharmacology

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