Cited by 165Nitric Oxide and Endothelin EffectsAdvanced Glycation End Products researchRedox biology and oxidative stress

Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction

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Szabo, Csaba·2009·British Journal of Pharmacology

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.

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Crossref · 10.1111/j.1476-5381.2008.00086.x

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  • This impairment includes esophageal ischemia and hypoxia secondary to microvascular changes and peroxynitrite-mediated endothelial and enteric neuron damage.

    “This impairment includes esophageal ischemia and hypoxia secondary to microvascular changes and peroxynitrite-mediated endothelial and enteric neuron damage [24], [25].”

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Authors
Szabo, C.
Venue
British Journal of Pharmacology
Publisher
Wiley
Published
2009-03
Volume
156
Issue
5
Pages
713-727
ISSN
  • 0007-1188 (ISSN-L)
  • 1476-5381
OpenAlex
W1601356608
Cited by
165
References
192
Citations by year
2026: 6 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 10 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 7 · 2015: 9 · 2014: 14 · 2013: 12 · 2012: 16
FWCI
2.19
Type
journal article
Language
en
Open access
Locations
  • British Journal of Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM060915)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
nitrosative stress, reactive nitrogen species, diabetic vascular complications, endothelial dysfunction, nitric oxide, peroxynitrite, mitochondrial superoxide, poly(ADP-ribose) polymerase, poly(ADP-ribosyl)ation, glyceraldehyde-3-phosphate dehydrogenase, advanced glycation end products, nuclear factor-kappaB, protein kinase C, vasorelaxation, diabetes mellitus
MeSH terms
Aldehyde Reductase, Angiotensin II, Animals, Diabetic Angiopathies, Drug Therapy, Combination, Endothelium, Vascular, Enzyme Activation, Glucose, Humans, Poly Adenosine Diphosphate Ribose, Protein Kinase C, Signal Transduction, Glycation End Products, Advanced, Reactive Oxygen Species, Oxidative Stress, Reactive Nitrogen Species, Peroxynitrous Acid

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