Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 Receptor
Background Elevated angiotensin II levels are thought to play an important role in atrial electrical and structural remodeling associated with atrial fibrillation. However, the mechanisms by which this remodeling occurs are still unclear. Accordingly, we explored the effects of angiotensin II on atr...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-04-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.023974 |
| _version_ | 1797301631026462720 |
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| author | Julie Demers Anh‐Tuan Ton François Huynh Simon Thibault Anique Ducharme Pierre Paradis Mona Nemer Céline Fiset |
| author_facet | Julie Demers Anh‐Tuan Ton François Huynh Simon Thibault Anique Ducharme Pierre Paradis Mona Nemer Céline Fiset |
| author_sort | Julie Demers |
| collection | DOAJ |
| description | Background Elevated angiotensin II levels are thought to play an important role in atrial electrical and structural remodeling associated with atrial fibrillation. However, the mechanisms by which this remodeling occurs are still unclear. Accordingly, we explored the effects of angiotensin II on atrial remodeling using transgenic mice overexpressing angiotensin II type 1 receptor (AT1R) specifically in cardiomyocytes. Methods and Results Voltage‐clamp techniques, surface ECG, programmed electrical stimulations along with quantitative polymerase chain reaction, Western blot, and Picrosirius red staining were used to compare the atrial phenotype of AT1R mice and their controls at 50 days and 6 months. Atrial cell capacitance and fibrosis were increased only in AT1R mice at 6 months, indicating the presence of structural remodeling. Ca2+ (ICaL) and K+ currents were not altered by AT1R overexpression (AT1R at 50 days). However, ICaL density and CaV1.2 messenger RNA expression were reduced by structural remodeling (AT1R at 6 months). Conversely, Na+ current (INa) was reduced (−65%) by AT1R overexpression (AT1R at 50 days) and the presence of structural remodeling (AT1R at 6 months) yields no further effect. The reduced INa density was not explained by lower NaV1.5 expression but was rather associated with an increase in sarcolemmal protein kinase C alpha expression in the atria, suggesting that chronic AT1R activation reduced INa through protein kinase C alpha activation. Furthermore, connexin 40 expression was reduced in AT1R mice at 50 days and 6 months. These changes were associated with delayed atrial conduction time, as evidenced by prolonged P‐wave duration. Conclusions Chronic AT1R activation leads to slower atrial conduction caused by reduced INa density and connexin 40 expression. |
| first_indexed | 2024-03-07T23:25:21Z |
| format | Article |
| id | doaj.art-01ecdbb6794f43fa8721720ef1e71bb0 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-07T23:25:21Z |
| publishDate | 2022-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-01ecdbb6794f43fa8721720ef1e71bb02024-02-21T04:32:43ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-04-0111810.1161/JAHA.121.023974Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 ReceptorJulie Demers0Anh‐Tuan Ton1François Huynh2Simon Thibault3Anique Ducharme4Pierre Paradis5Mona Nemer6Céline Fiset7Research Center Montreal Heart Institute Montréal Québec CanadaResearch Center Montreal Heart Institute Montréal Québec CanadaResearch Center Montreal Heart Institute Montréal Québec CanadaResearch Center Montreal Heart Institute Montréal Québec CanadaResearch Center Montreal Heart Institute Montréal Québec CanadaMcGill University Montréal Québec CanadaUniversity of Ottawa Ottawa CanadaResearch Center Montreal Heart Institute Montréal Québec CanadaBackground Elevated angiotensin II levels are thought to play an important role in atrial electrical and structural remodeling associated with atrial fibrillation. However, the mechanisms by which this remodeling occurs are still unclear. Accordingly, we explored the effects of angiotensin II on atrial remodeling using transgenic mice overexpressing angiotensin II type 1 receptor (AT1R) specifically in cardiomyocytes. Methods and Results Voltage‐clamp techniques, surface ECG, programmed electrical stimulations along with quantitative polymerase chain reaction, Western blot, and Picrosirius red staining were used to compare the atrial phenotype of AT1R mice and their controls at 50 days and 6 months. Atrial cell capacitance and fibrosis were increased only in AT1R mice at 6 months, indicating the presence of structural remodeling. Ca2+ (ICaL) and K+ currents were not altered by AT1R overexpression (AT1R at 50 days). However, ICaL density and CaV1.2 messenger RNA expression were reduced by structural remodeling (AT1R at 6 months). Conversely, Na+ current (INa) was reduced (−65%) by AT1R overexpression (AT1R at 50 days) and the presence of structural remodeling (AT1R at 6 months) yields no further effect. The reduced INa density was not explained by lower NaV1.5 expression but was rather associated with an increase in sarcolemmal protein kinase C alpha expression in the atria, suggesting that chronic AT1R activation reduced INa through protein kinase C alpha activation. Furthermore, connexin 40 expression was reduced in AT1R mice at 50 days and 6 months. These changes were associated with delayed atrial conduction time, as evidenced by prolonged P‐wave duration. Conclusions Chronic AT1R activation leads to slower atrial conduction caused by reduced INa density and connexin 40 expression.https://www.ahajournals.org/doi/10.1161/JAHA.121.023974angiotensin II type 1 receptoratrial conductionconnexinsprotein kinase C alphasodium current |
| spellingShingle | Julie Demers Anh‐Tuan Ton François Huynh Simon Thibault Anique Ducharme Pierre Paradis Mona Nemer Céline Fiset Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 Receptor Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease angiotensin II type 1 receptor atrial conduction connexins protein kinase C alpha sodium current |
| title | Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 Receptor |
| title_full | Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 Receptor |
| title_fullStr | Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 Receptor |
| title_full_unstemmed | Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 Receptor |
| title_short | Atrial Electrical Remodeling in Mice With Cardiac‐Specific Overexpression of Angiotensin II Type 1 Receptor |
| title_sort | atrial electrical remodeling in mice with cardiac specific overexpression of angiotensin ii type 1 receptor |
| topic | angiotensin II type 1 receptor atrial conduction connexins protein kinase C alpha sodium current |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.023974 |
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