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

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology Pub Date : 2024-09-12 DOI:10.1016/j.redox.2024.103347

Lorenzo Loffredo , Annarosa Soresina , Bianca Laura Cinicola , Martina Capponi , Francesca Salvatori , Simona Bartimoccia , Vittorio Picchio , Maurizio Forte , Caterina Caputi , Roberto Poscia , Vincenzo Leuzzi , Alberto Spalice , Pasquale Pignatelli , Raffaele Badolato , Marzia Duse , Francesco Violi , Roberto Carnevale , Anna Maria Zicari

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Abstract

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

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 (H₂O₂) production, and hydrogen breakdown activity (HBA). Thrombus formation was assessed through the Total Thrombus Formation Analysis System (T-TAS).

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 H₂O₂ as compared to controls. Compared to the respective controls, AT children and their parents, who carried heterozygous ATM mutation, showed an accelerated thrombus growth as revealed by reduced occlusion time. Multivariable linear regression analysis revealed that sNOX2 (standardized coefficient β: −0.296; SE: 0.044; p = 0.002) and NO bioavailability (standardized coefficient β: 0.224; SE: 0.065; p = 0.02) emerged as the only independent predictive variables associated with FMD (R²: 0.44).

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.

Abstract Image

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共济失调性脊髓侧索硬化症（ATM）激酶突变患者动脉扩张受损，NOX2产生的氧化应激增加

背景编码ATM激酶的共济失调性脊髓侧索硬化症突变（ATM）基因发生突变的受试者更容易患动脉粥样硬化，但这一现象背后的机制尚不清楚。NADPH 氧化酶 2 型可能在这一过程中发挥作用，导致内皮功能障碍和血栓形成易感性增加。在这项横断面研究中，27 名共济失调毛细血管扩张症（AT）患儿（13 名男性和 14 名女性，平均年龄为 15.1 ± 7.6 岁）与 27 名年龄和性别匹配的对照组患儿（13 名男性和 14 名女性，平均年龄为 14.6 ± 8.4 岁）进行了比较。此外，研究还纳入了29名ATM（h-ATM）基因杂合突变的AT父母和29名年龄和性别匹配的对照组。内皮功能通过肱动脉血流介导的扩张（FMD）和一氧化氮（NO）生物利用度评估进行评价。氧化应激通过测量血清中可溶性 NOX2-dp（sNOX2-dp）的活性、过氧化氢（H2O2）的产生和氢分解活性（HBA）进行评估。通过血栓形成总分析系统（T-TAS）评估血栓形成情况。结果与年龄和性别匹配的对照组相比，AT 儿童及其父母的杂合性 ATM 突变表现出明显较低的 FMD、HBA 和 NO 生物利用率。与对照组相比，AT儿童和ATM杂合突变携带者的sNOX2-dp和H2O2浓度明显更高。与相应的对照组相比，携带杂合性ATM突变的AT儿童及其父母的血栓生长速度加快，闭塞时间缩短。多变量线性回归分析显示，sNOX2（标准化系数β：-0.296；SE：0.044；P = 0.002）和 NO 生物利用率（标准化系数β：0.224；SE：0.065；P = 0.结论本研究表明，ATM 基因突变患者会出现内皮功能障碍、氧化应激增加和血栓形成增加。这些因素共同导致这些人更易患动脉粥样硬化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

19.90

自引率

3.50%

发文量

318

审稿时长

25 days

期刊介绍： Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.