eNOS uncoupling drives oxidative stress and arrhythmogenic vulnerability in experimental hypothyroidism
7 affiliations
- 1Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil; Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil; Co-corresponding author. Department of Physiology, Federal University of Sergipe. Av. Marechal Rondon, S/N, Rosa Elze, Aracaju, SE, Brazil.
- 2Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
- 3Department of Pharmacology, Federal University of Minas Gerais, Belo Horizonte, Brazil
- 4Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil
- 5Immunology Center, Institute Adolfo Lutz, São Paulo, Brazil
- 6Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
- 7Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil; Corresponding author. Department of Biophysics, Federal University of Sao Paulo, Botucatu Street, 862, Biological Science Building, Sao Paulo, SP, Brazil.
Abstract
Aims: Cardiac arrhythmias are a major cause of morbidity and sudden cardiac death worldwide, and hypothyroidism has emerged as an important risk factor. Among the mechanisms involved in cardiac electrical stability, nitric oxide (NO) signaling, particularly via endothelial nitric oxide synthase (eNOS), plays a critical role in cardiac excitation–contraction coupling. Here, we investigated whether hypothyroidism increases susceptibility to stress-induced arrhythmias through eNOS uncoupling and excessive reactive oxygen species (ROS) production. Methods and results: Hypothyroidism was induced in Swiss mice by methimazole administration in the drinking water for 21 days. In vivo electrocardiographic recordings revealed a marked increase in stress-induced arrhythmias following dobutamine/caffeine challenge. At the cellular level, left ventricular cardiomyocytes from hypothyroid mice exhibited elevated ROS production, electrical instability, enhanced Na + and Ca 2+ currents, and reduced repolarizing K + currents, resulting in action potential prolongation. Unbalanced oxidative stress was associated with redox-dependent Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activation, contributing to intracellular Ca 2+ instability and triggered activity in cardiomyocytes. Mechanistically, hypothyroidism promotedeNOS uncoupling in cardiomyocytes, evidenced by a reduced eNOS dimer/monomer ratio, leading to increasedROSgeneration and impaired NO production. Pharmacological restoration of eNOS coupling with tetrahydrobiopterin (BH4) normalized ROS and NO at the cellular level, attenuated redox-dependent CaMKII activation, and significantly reduced arrhythmia incidence in vivo . Conclusion: Together, these findings demonstrate that eNOS uncoupling is a key driver of oxidative stress and arrhythmogenic vulnerability in experimental hypothyroidism, suggesting that restoration of eNOS coupling may represent a potential therapeutic strategy to reduce arrhythmogenic risk in hypothyroidism.
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BibTeX
@article{souza2026enos,
title = {{eNOS uncoupling drives oxidative stress and arrhythmogenic vulnerability in experimental hypothyroidism}},
author = {Diego Santos Souza and Leisiane Pereira Marques and Aimée Obolari Durço and Fabiana da Silva Alcântara and Diego José Belato Orts and Melissa Tainan Silva Dias and Michael Ramon de Lima Conceiçao and Jorge Lucas Teixeira-Fonseca and Luiz Fernando Santos Matos and Maria Luiza Alarcon Mady Barbosa and Daiara Custódio Santos and Luciano dos Santos Aggum Capettini and Carlos Roberto Prudencio and Danilo Lustrino and Jader Santos Cruz and Danilo Roman-Campos},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104447},
url = {https://doi.org/10.1016/j.redox.2026.104447},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - eNOS uncoupling drives oxidative stress and arrhythmogenic vulnerability in experimental hypothyroidism
AU - Diego Santos Souza
AU - Leisiane Pereira Marques
AU - Aimée Obolari Durço
AU - Fabiana da Silva Alcântara
AU - Diego José Belato Orts
AU - Melissa Tainan Silva Dias
AU - Michael Ramon de Lima Conceiçao
AU - Jorge Lucas Teixeira-Fonseca
AU - Luiz Fernando Santos Matos
AU - Maria Luiza Alarcon Mady Barbosa
AU - Daiara Custódio Santos
AU - Luciano dos Santos Aggum Capettini
AU - Carlos Roberto Prudencio
AU - Danilo Lustrino
AU - Jader Santos Cruz
AU - Danilo Roman-Campos
PY - 2026
DA - 2026/10/20
JO - Redox Biology
DO - 10.1016/j.redox.2026.104447
UR - https://doi.org/10.1016/j.redox.2026.104447
AB - Aims: Cardiac arrhythmias are a major cause of morbidity and sudden cardiac death worldwide, and hypothyroidism has emerged as an important risk factor. Among the mechanisms involved in cardiac electrical stability, nitric oxide (NO) signaling, particularly via endothelial nitric oxide synthase (eNOS), plays a critical role in cardiac excitation–contraction coupling. Here, we investigated whether hypothyroidism increases susceptibility to stress-induced arrhythmias through eNOS uncoupling and excessive reactive oxygen species (ROS) production. Methods and results: Hypothyroidism was induced in Swiss mice by methimazole administration in the drinking water for 21 days. In vivo electrocardiographic recordings revealed a marked increase in stress-induced arrhythmias following dobutamine/caffeine challenge. At the cellular level, left ventricular cardiomyocytes from hypothyroid mice exhibited elevated ROS production, electrical instability, enhanced Na + and Ca 2+ currents, and reduced repolarizing K + currents, resulting in action potential prolongation. Unbalanced oxidative stress was associated with redox-dependent Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activation, contributing to intracellular Ca 2+ instability and triggered activity in cardiomyocytes. Mechanistically, hypothyroidism promotedeNOS uncoupling in cardiomyocytes, evidenced by a reduced eNOS dimer/monomer ratio, leading to increasedROSgeneration and impaired NO production. Pharmacological restoration of eNOS coupling with tetrahydrobiopterin (BH4) normalized ROS and NO at the cellular level, attenuated redox-dependent CaMKII activation, and significantly reduced arrhythmia incidence in vivo . Conclusion: Together, these findings demonstrate that eNOS uncoupling is a key driver of oxidative stress and arrhythmogenic vulnerability in experimental hypothyroidism, suggesting that restoration of eNOS coupling may represent a potential therapeutic strategy to reduce arrhythmogenic risk in hypothyroidism.
SN - 2213-2317
ER -