Impaired arterial dilation and increased NOX2 generated oxidative stress in subjects with ataxia-telangiectasia mutated (ATM) kinase.

Journal

Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639

Informations de publication

Date de publication:
12 Sep 2024
Historique:
received: 07 08 2024
revised: 04 09 2024
accepted: 07 09 2024
medline: 26 9 2024
pubmed: 26 9 2024
entrez: 26 9 2024
Statut: aheadofprint

Résumé

Subjects with mutations in the Ataxia-Telangiectasia mutated (ATM) gene encoding for ATM kinase have a greater predisposition to develop atherosclerosis, but the mechanism behind this phenomenon is not yet understood. NADPH oxidase type 2 may play a role in this process, leading to endothelial dysfunction and an increased susceptibility to thrombosis. The purpose of this study was to assess the redox state in individuals with ATM mutations and determine its impact on endothelial function. In this cross-sectional study, twenty-seven children with ataxia telangiectasia (AT) (13 males and 14 females, mean age 15.1 ± 7.6 years) were compared with 27 controls (13 males and 14 females, mean age 14.6 ± 8.4 years) matched for age and gender. Additionally, 29 AT parents with heterozygous mutation of ATM (h-ATM) gene, and 29 age- and gender-matched controls were included. Endothelial function was evaluated through brachial flow-mediated dilation (FMD) and the assessment of nitric oxide (NO) bioavailability. Oxidative stress was evaluated by measuring serum activity of soluble NOX2-dp (sNOX2-dp), hydrogen peroxide (H AT children and parents with heterozygous ATM mutations exhibited significantly lower FMD, HBA, and NO bioavailability as compared to age and gender matched controls. AT children and ATM carrier of heterozygous ATM mutations had significantly higher concentrations of sNOX2-dp and H This study demonstrates that individuals with ATM mutations experience endothelial dysfunction, increased oxidative stress, and elevated thrombus formation. These factors collectively contribute to the heightened susceptibility of these individuals to develop atherosclerosis.

Sections du résumé

BACKGROUND BACKGROUND
Subjects with mutations in the Ataxia-Telangiectasia mutated (ATM) gene encoding for ATM kinase have a greater predisposition to develop atherosclerosis, but the mechanism behind this phenomenon is not yet understood. NADPH oxidase type 2 may play a role in this process, leading to endothelial dysfunction and an increased susceptibility to thrombosis. The purpose of this study was to assess the redox state in individuals with ATM mutations and determine its impact on endothelial function.
METHODS METHODS
In this cross-sectional study, twenty-seven children with ataxia telangiectasia (AT) (13 males and 14 females, mean age 15.1 ± 7.6 years) were compared with 27 controls (13 males and 14 females, mean age 14.6 ± 8.4 years) matched for age and gender. Additionally, 29 AT parents with heterozygous mutation of ATM (h-ATM) gene, and 29 age- and gender-matched controls were included. Endothelial function was evaluated through brachial flow-mediated dilation (FMD) and the assessment of nitric oxide (NO) bioavailability. Oxidative stress was evaluated by measuring serum activity of soluble NOX2-dp (sNOX2-dp), hydrogen peroxide (H
RESULTS RESULTS
AT children and parents with heterozygous ATM mutations exhibited significantly lower FMD, HBA, and NO bioavailability as compared to age and gender matched controls. AT children and ATM carrier of heterozygous ATM mutations had significantly higher concentrations of sNOX2-dp and H
CONCLUSIONS CONCLUSIONS
This study demonstrates that individuals with ATM mutations experience endothelial dysfunction, increased oxidative stress, and elevated thrombus formation. These factors collectively contribute to the heightened susceptibility of these individuals to develop atherosclerosis.

Identifiants

DOI: 10.1016/j.redox.2024.103347 PMID: 39326070
pubmed: 39326070
pii: S2213-2317(24)00325-2
doi: 10.1016/j.redox.2024.103347
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

103347

Investigateurs

Ilaria Maria Palumbo (IM)
Arianna Magna (A)
Alessia Fallarino (A)
Arianna Pannunzio (A)
Enrico Maggio (E)
Chiara Bagnato (C)
Vittoria Cammisotto (V)
Valentina Castellani (V)

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare no conflict of interest.

Auteurs

Lorenzo Loffredo (L)

Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy. Electronic address: lorenzo.loffredo@uniroma1.it.

Annarosa Soresina (A)

Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia and ASST-Spedali Civili di Brescia, Brescia, Italy.

Bianca Laura Cinicola (BL)

Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy.

Martina Capponi (M)

Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy.

Francesca Salvatori (F)

Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy.

Simona Bartimoccia (S)

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.

Vittorio Picchio (V)

IRCCS Neuromed, Pozzilli (IS), Italy.

Maurizio Forte (M)

IRCCS Neuromed, Pozzilli (IS), Italy.

Caterina Caputi (C)

Department of Human Neuroscience - Unit of Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.

Roberto Poscia (R)

Clinical Research Unit, AOU Policlinico Umberto I- Sapienza University of Rome, Rome, Italy.

Vincenzo Leuzzi (V)

Department of Human Neuroscience - Unit of Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.

Alberto Spalice (A)

Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy.

Pasquale Pignatelli (P)

Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy.

Raffaele Badolato (R)

Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia and ASST-Spedali Civili di Brescia, Brescia, Italy.

Marzia Duse (M)

Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy.

Francesco Violi (F)

Sapienza University of Rome, Rome, Italy.

Roberto Carnevale (R)

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; IRCCS Neuromed, Pozzilli (IS), Italy.

Anna Maria Zicari (AM)

Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy.

Classifications MeSH