Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction
Open accessAbstract
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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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].”
From Cytoprotective Effects of Hydrogen Sulfide in Novel Rat Models of Non-Erosive Esophagitis (2014) · cites this paper as [25]
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Coletta, C., Papapetropoulos, A., Erdelyi, K., Olah, G., Módis, K., Panopoulos, P., Asimakopoulou, A., Gerö, D., Sharina, I., Martin, E., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1202916109 · Cited by 677 · see citing works
Self-citationTargeting vascular (endothelial) dysfunction
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Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond
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Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide
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Cell signaling mediated by nitrated cyclic guanine nucleotide
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“This impairment includes esophageal ischemia and hypoxia secondary to microvascular changes and peroxynitrite-mediated endothelial and enteric neuron damage [24,25].”
Background
- 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
- PMC
- PMC2697759
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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