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Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets
Abstract
Nitric oxide (NO) is one of the most important molecules released by endothelial cells, and its antiatherogenic properties support cardiovascular homeostasis. Diminished NO bioavailability is a common hallmark of endothelial dysfunction underlying the patho‑ genesis of the cardiovascular disease. Vascular NO is synthesized by endothelial nitric oxide synthase (eNOS) from the substrate L‑arginine (L‑Arg), with tetrahydrobiopterin (BH4) as an essential cofactor. Cardiovascular risk factors such as diabetes, dyslipidemia, hypertension, aging, or smoking increase vascular oxidative stress that strongly affects eNOS activity and leads to eNOS uncoupling. Uncoupled eNOS produces superoxide anion (O2−) instead of NO, thus becoming a source of harmful free radicals exacerbat‑ ing the oxidative stress further. eNOS uncoupling is thought to be one of the major underlying causes of endothelial dysfunction observed in the pathogenesis of vascular diseases. Here, we discuss the main mechanisms of eNOS uncoupling, including oxida‑ tive depletion of the critical eNOS cofactor BH4, deficiency of eNOS substrate L‑Arg, or accumulation of its analog asymmetrical dimethylarginine (ADMA), and eNOS S‑glu‑ tathionylation. Moreover, potential therapeutic approaches that prevent eNOS uncou‑ pling by improving cofactor availability, restoration of L‑Arg/ADMA ratio, or modulation of eNOS S‑glutathionylation are briefly outlined.
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Authors (5)
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Anna Janaszak-Jasiecka
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Agata Płoska
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Joanna M. Wierońska
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Lawrence W. Dobrucki
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Full text
- Publication version
- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1186/s11658-023-00423-2
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- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
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CELLULAR & MOLECULAR BIOLOGY LETTERS
no. 28,
ISSN: 1425-8153 - Language:
- English
- Publication year:
- 2023
- Bibliographic description:
- Janaszak-Jasiecka A., Płoska A., Wierońska J. M., Dobrucki L. W., Kalinowski L.: Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets// CELLULAR & MOLECULAR BIOLOGY LETTERS -Vol. 28,iss. 1 (2023),
- DOI:
- Digital Object Identifier (open in new tab) 10.1186/s11658-023-00423-2
- Sources of funding:
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- This study was supported by the Polish National Science Centre (NCN) OPUS Grant Nos. 2015/19/B/NZ7/03830 and 2019/33/B/NZ7/02699, and by the Ministry of Education and Science Poland Grant No. 10/E‑389/SPUB/SP/2020.
- Verified by:
- Gdańsk University of Technology
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