Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction
Abstract Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in male HFpEF hearts. Genetic suppr...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56186-1 |
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| author | Thassio Mesquita Rodrigo Miguel-dos-Santos Weixin Liu Mario Fournier Russell G. Rogers Jocelyn Alfaro Asma Nawaz Lizbeth Sanchez Xaviar M. Jones Liang Li Eduardo Marbán Eugenio Cingolani |
| author_facet | Thassio Mesquita Rodrigo Miguel-dos-Santos Weixin Liu Mario Fournier Russell G. Rogers Jocelyn Alfaro Asma Nawaz Lizbeth Sanchez Xaviar M. Jones Liang Li Eduardo Marbán Eugenio Cingolani |
| author_sort | Thassio Mesquita |
| collection | DOAJ |
| description | Abstract Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in male HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic remodeling and cardiomyocyte-fibroblast communication can be corrected, constituting an alternative therapeutic strategy for HFpEF. |
| format | Article |
| id | doaj-art-2c86f32dbecd4e1290615847996e1675 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2c86f32dbecd4e1290615847996e16752025-02-02T12:32:45ZengNature PortfolioNature Communications2041-17232025-01-0116111310.1038/s41467-025-56186-1Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fractionThassio Mesquita0Rodrigo Miguel-dos-Santos1Weixin Liu2Mario Fournier3Russell G. Rogers4Jocelyn Alfaro5Asma Nawaz6Lizbeth Sanchez7Xaviar M. Jones8Liang Li9Eduardo Marbán10Eugenio Cingolani11Smidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesSmidt Heart Institute, Cedars-Sinai Medical Center, Los AngelesAbstract Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in male HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic remodeling and cardiomyocyte-fibroblast communication can be corrected, constituting an alternative therapeutic strategy for HFpEF.https://doi.org/10.1038/s41467-025-56186-1 |
| spellingShingle | Thassio Mesquita Rodrigo Miguel-dos-Santos Weixin Liu Mario Fournier Russell G. Rogers Jocelyn Alfaro Asma Nawaz Lizbeth Sanchez Xaviar M. Jones Liang Li Eduardo Marbán Eugenio Cingolani Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction Nature Communications |
| title | Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction |
| title_full | Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction |
| title_fullStr | Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction |
| title_full_unstemmed | Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction |
| title_short | Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction |
| title_sort | upregulated foxo1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction |
| url | https://doi.org/10.1038/s41467-025-56186-1 |
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