FoxO1 is required for high glucose-dependent cardiac fibroblasts into myofibroblast phenoconversion

Raúl Vivar, Renatto Anfossi, Claudio Humeres, Mabel Catalán, Christopher Reyes, Simone Cárdenas, Alejandra Contreras, Pablo Aránguiz, Fabiola González, Guillermo Diaz-Araya

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


In the normal heart, cardiac fibroblasts (CFs) maintain extracellular matrix (ECM) homeostasis, whereas in pathological conditions, such as diabetes mellitus (DM), CFs converse into cardiac myofibroblasts (CMFs) and this CFs phenoconversion increase the synthesis and secretion of ECM proteins, promoting cardiac fibrosis and heart dysfunction. High glucose (HG) conditions increase TGF-β1 expression and FoxO1 activity, whereas FoxO1 is crucial to CFs phenoconversion induced by TGF-β1. In addition, FoxO1 increases CTGF expression, whereas CTGF plays an active role in the fibrotic process induced by hyperglycemia. However, the role of FoxO1 and CTGF in CFs phenoconversion induced by HG is not clear. In this study, we investigated the effects of FoxO1 pharmacological inhibition on CFs phenoconversion in both in vitro and ex vivo models of DM. Our results demonstrate that HG induces CFs phenoconversion and FoxO1 activation. Moreover, AS1842856, a pharmacological inhibitor of FoxO1 activity, prevents CFs phenoconversion and CTGF expression increase induced by HG, whereas these results were corroborated by FoxO1 silencing. Additionally, K252a, a pharmacological blocker of CTGF receptor, prevents HG-induced CFs phenoconversion, which was corroborated with CTGF expression knockdown. Furthermore, through CFs isolation from heart of diabetic rats, we showed that hyperglycemia induces FoxO1 activation, the increase of CTGF expression and CFs phenoconversion, whereas the FoxO1 activity inhibition reverses the effects induced by hyperglycemia on CFs. Altogether, our results demonstrate that FoxO1 and CTGF are necessary for CFs phenoconversion induced by HG and suggest that both proteins are likely to become a potential targeted drug for fibrotic response induced by hyperglycemic conditions.

Original languageEnglish
Article number109978
JournalCellular Signalling
Publication statusPublished - Jul 2021


  • Cardiac fibroblast
  • Cardiac fibrosis
  • CFs phenoconversion
  • CTGF
  • Diabetes mellitus
  • FoxO1
  • High glucose

ASJC Scopus subject areas

  • Cell Biology


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