Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress
Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the at...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2021-12-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.147371 |
| _version_ | 1811227237229264896 |
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| author | Uma Mahesh R. Avula Haikel Dridi Bi-xing Chen Qi Yuan Alexander N. Katchman Steven R. Reiken Amar D. Desai Samantha Parsons Haajra Baksh Elaine Ma Parmanand Dasrat Ruiping Ji Yejun Lin Christine Sison W. Jonathan Lederer Humberto C. Joca Christopher W. Ward Maura Greiser Andrew R. Marks Steven O. Marx Elaine Y. Wan |
| author_facet | Uma Mahesh R. Avula Haikel Dridi Bi-xing Chen Qi Yuan Alexander N. Katchman Steven R. Reiken Amar D. Desai Samantha Parsons Haajra Baksh Elaine Ma Parmanand Dasrat Ruiping Ji Yejun Lin Christine Sison W. Jonathan Lederer Humberto C. Joca Christopher W. Ward Maura Greiser Andrew R. Marks Steven O. Marx Elaine Y. Wan |
| author_sort | Uma Mahesh R. Avula |
| collection | DOAJ |
| description | Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current–induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress. |
| first_indexed | 2024-04-12T09:38:06Z |
| format | Article |
| id | doaj.art-b7be647bfebd45409f3562f2a31b359c |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:38:06Z |
| publishDate | 2021-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b7be647bfebd45409f3562f2a31b359c2022-12-22T03:38:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-12-01623Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stressUma Mahesh R. AvulaHaikel DridiBi-xing ChenQi YuanAlexander N. KatchmanSteven R. ReikenAmar D. DesaiSamantha ParsonsHaajra BakshElaine MaParmanand DasratRuiping JiYejun LinChristine SisonW. Jonathan LedererHumberto C. JocaChristopher W. WardMaura GreiserAndrew R. MarksSteven O. MarxElaine Y. WanMechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current–induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.https://doi.org/10.1172/jci.insight.147371Cardiology |
| spellingShingle | Uma Mahesh R. Avula Haikel Dridi Bi-xing Chen Qi Yuan Alexander N. Katchman Steven R. Reiken Amar D. Desai Samantha Parsons Haajra Baksh Elaine Ma Parmanand Dasrat Ruiping Ji Yejun Lin Christine Sison W. Jonathan Lederer Humberto C. Joca Christopher W. Ward Maura Greiser Andrew R. Marks Steven O. Marx Elaine Y. Wan Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress JCI Insight Cardiology |
| title | Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress |
| title_full | Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress |
| title_fullStr | Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress |
| title_full_unstemmed | Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress |
| title_short | Attenuating persistent sodium current–induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress |
| title_sort | attenuating persistent sodium current induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress |
| topic | Cardiology |
| url | https://doi.org/10.1172/jci.insight.147371 |
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