Role of FoxO3a as a negative regulator of the cardiac myofibroblast conversion induced by TGF-β1

Raúl Vivar, Claudio Humeres, Renatto Anfossi, Samir Bolivar, Mabel Catalán, Joseph Hill, Sergio Lavandero, Guillermo Diaz-Araya

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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-β1 is a key protein involved in CMF conversion. SMADs are nuclear factor proteins activated by TGF-β1 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-β1-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-β1 decreases the activation and expression of FoxO3a in CFs. FoxO3a regulation by TGF-β1 requires activated SMAD3, ERK1/2 and Akt. Furthermore, we show that FoxO1 is crucial in the FoxO3a regulation induced by TGF-β1, as shown by overexpressed FoxO1 enhancing and silenced FoxO1 suppressing the effects of TGF-β1 on FoxO3a. Finally, the regulation of TGF-β1-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-β1.

Original languageEnglish (US)
Article number118695
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1867
Issue number7
DOIs
StatePublished - Jul 2020

Keywords

  • Cardiac fibroblast
  • FoxO1, cell differentiation
  • FoxO3a
  • TGF-β1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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