Impaired arterial dilation and increased NOX2 generated oxidative stress in subjects with ataxia-telangiectasia mutated (ATM) kinase
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,
Ilaria Maria Palumbo,
Arianna Magna,
Alessia Fallarino,
Arianna Pannunzio,
Enrico Maggio,
Chiara Bagnato,
Vittoria Cammisotto,
Valentina Castellani
Affiliations
Lorenzo Loffredo
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy; Corresponding author. Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Viale del Policlinico 155, Rome, 00161, Italy.
Annarosa Soresina
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
Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy
Martina Capponi
Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy
Francesca Salvatori
Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy
Simona Bartimoccia
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
Vittorio Picchio
IRCCS Neuromed, Pozzilli (IS), Italy
Maurizio Forte
IRCCS Neuromed, Pozzilli (IS), Italy
Caterina Caputi
Department of Human Neuroscience - Unit of Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
Roberto Poscia
Clinical Research Unit, AOU Policlinico Umberto I- Sapienza University of Rome, Rome, Italy
Vincenzo Leuzzi
Department of Human Neuroscience - Unit of Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
Alberto Spalice
Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy
Pasquale Pignatelli
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Raffaele Badolato
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
Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy
Francesco Violi
Sapienza University of Rome, Rome, Italy
Roberto Carnevale
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; IRCCS Neuromed, Pozzilli (IS), Italy
Anna Maria Zicari
Department of Maternal, Child Health and Urological Sciences, Sapienza University, Rome, Italy
Ilaria Maria Palumbo
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Arianna Magna
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Alessia Fallarino
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Arianna Pannunzio
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Enrico Maggio
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Chiara Bagnato
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Vittoria Cammisotto
Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Italy
Valentina Castellani
Department of General Surgery and Surgical Specialty, Sapienza University of Rome, Rome, Italy; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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.
