Role of FoxO3a as a negative regulator of the cardiac myofibroblast conversion induced by TGF-β1
Author
dc.contributor.author
Vivar Sánchez, Raúl
Author
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Humeres, Claudio
Author
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Anfossi, Renatto
Author
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Bolívar, Samir
Author
dc.contributor.author
Catalán Díaz, Mabel
Author
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Hill, Joseph
Author
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Lavandero González, Sergio
Author
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Díaz Araya, Guillermo
Admission date
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2020-07-02T02:19:28Z
Available date
dc.date.available
2020-07-02T02:19:28Z
Publication date
dc.date.issued
2020
Cita de ítem
dc.identifier.citation
BBA - Molecular Cell Research 1867 (2020) 118695
es_ES
Identifier
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10.1016/j.bbamcr.2020.118695
Identifier
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https://repositorio.uchile.cl/handle/2250/175742
Abstract
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Cardiac fibroblasts (CFs) are necessary to maintain extracellular matrix (ECM) homeostasis in the heart. Normally, CFs are quiescent and secrete small amounts of ECM components, whereas, in pathological conditions, they differentiate into more active cells called cardiac myofibroblasts (CMF). CMF conversion is characteristic of cardiac fibrotic diseases, such as heart failure and diabetic cardiomyopathy. TGF-beta 1 is a key protein involved in CMF conversion. SMADs are nuclear factor proteins activated by TGF-beta 1 that need other proteins, such as forkhead box type O (FoxO) family members, to promote CMF conversion. FoxO1, a member of this family protein, is necessary for TGF-beta 1-induced CMF conversion, whereas the role of FoxO3a, another FoxO family member, is unknown. FoxO3a plays an important role in many fibrotic processes in the kidney and lung. However, the participation of FoxO3a in the conversion of CFs into CMF is not clear. In this paper, we demonstrate that TGF-beta 1 decreases the activation and expression of FoxO3a in CFs. FoxO3a regulation by TGF-ss 1 requires activated SMAD3, ERK1/2 and Akt. Furthermore, we show that FoxO1 is crucial in the FoxO3a regulation induced by TGF-beta 1, as shown by overexpressed FoxO1 enhancing and silenced FoxO1 suppressing the effects of TGF-beta 1 on FoxO3a. Finally, the regulation of TGF-beta 1-induced CMF conversion was enhanced by FoxO3a silencing and suppressed by inhibited FoxO3a degradation. Considering these collective findings, we suggest that FoxO3a acts as a negative regulator of the CMF conversion that is induced by TGF-beta 1.
es_ES
Patrocinador
dc.description.sponsorship
Consejo Nacional de Ciencia y Tecnologia (CONACyT)
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
FONDECYT 11160531
FONDECYT 11160281
FONDECYT 1170425
Vicerrectoria de Investigacion y Desarrollo, Universidad de Chile
UI-15/16