Addressing Complexity in Pulmonary Hypertension: The FoxO1 Case.

Abstract

Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension Savai et al Nat Medicine . 2014;20:1289–1300. > “…We think Android is very fragmented and becoming more fragmented by the day. We think integrated will trump fragmented every time…” > > Steve Jobs (on iPhone) Pulmonary arterial hypertension (PAH) is a mysterious killer that, like cancer, is characterized by tremendous complexity. A myriad of apparently unrelated molecular abnormalities have been described but, perhaps because of this complexity, the progress in PAH drug development suffers from poor bench-to-bedside translation.1 Savai et al,2 attacked the master transcription factor forkhead box O1 (FoxO1), arguing that targeting more proximal hubs that integrate many mechanisms in the PAH pathogenesis cascade will be more effective than attacking individual distal targets. It is not the first time that this has been attempted in PAH. Master transcription factors like nuclear factor of activated T-cell c2 (NFATc2),3 hypoxia inducible factor 1α (HIF-1α),4 and signal transducer and activator of transcription 3 (STAT3)5 have effectively been targeted in PAH models. Attempts to integrate this fragmented field, like the metabolic6 and inflammatory7 theories of PAH, have emerged. The Fox-containing proteins are a diverse family of ≥100 transcription factors that can integrate many cellular signals.8 Their diversity ensures their ability to fine tune gene transcription in health, development, and common diseases like cancer. The most studied, that is, the FoxO family, are bona fide tumor suppressors and are almost ubiquitously expressed.8 FoxO factors mediate G1 phase cell-cycle arrest and G2/M cell-cycle phase transition; they are also important in inflammation, metabolism, and vascular homeostasis (Figure). FoxOs are inhibited by phosphorylation that creates a binding motif for the 14-3-3 scaffolding proteins, causing FoxO1 exclusion from the nucleus, promoting their cytoplasmic ubiquination and degradation.8 Acetylation also attenuates …