The FoxO family in cardiac function and dysfunction

Abstract

The Forkhead family of transcription factors mediates many aspects of physiology, including stress response, metabolism, commitment to apoptosis, and development. The Forkhead box subfamily O (FoxO) proteins have garnered particular interest due to their involvement in the modulation of cardiovascular biology. In this review, we discuss the mechanisms of FoxO regulation and outcomes of FoxO signaling under normal and pathological cardiovascular contexts.

Figure 1

Akt and FoxO signaling pathways in cardiac hypertrophy. (a) Insulin receptor signaling activates the PI3K (phosphoinositide-3 kinase) signaling cascade, leading to Akt phosphorylation and translocation into the nucleus. Akt phosphorylates three conserved FoxO residues to promote FoxO association with 14-3-3 proteins and nuclear export to the cytosol, where the complex remains transcriptionally inactive. Calcineurin dephosphorylates NFAT (nuclear factor of activated T cells), allowing NFAT nuclear translocation and subsequent transcription of NFAT target genes, such as those encoding α-skeletal actin and β-myosin heavy chain. PP2A and calcineurin provide negative feedback by dephosphorylating Akt. (b) In the absence of PI3K signaling, FoxO is able to transcribe target genes such as atrogin-1, which encodes a ubiquitin ligase that promotes calcineurin degradation and prevents NFAT activation. The decrease in calcineurin levels reduces Akt-associated phosphatase activity. FoxO also reduces PP2A phosphatase activity on Akt. The reduction in calcineurin and PP2A-associated phosphatase activity leads to Akt hyperphosphorylation, which eventually inhibits FoxO activity.