Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction

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 and Eugenio Cingolani ()
Additional contact information
Thassio Mesquita: Los Angeles
Rodrigo Miguel-dos-Santos: Los Angeles
Weixin Liu: Los Angeles
Mario Fournier: Los Angeles
Russell G. Rogers: Los Angeles
Jocelyn Alfaro: Los Angeles
Asma Nawaz: Los Angeles
Lizbeth Sanchez: Los Angeles
Xaviar M. Jones: Los Angeles
Liang Li: Los Angeles
Eduardo Marbán: Los Angeles
Eugenio Cingolani: Los Angeles

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56186-1

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DOI: 10.1038/s41467-025-56186-1

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