Researchers Identify Protein That Could Help Further Explore Metabolic and Inflammatory Theories Behind PAH Development

Two theories behind the pathogenesis of pulmonary arterial hypertension (PAH) converge on the protein known as the master transcription factor forkhead box O1 (FoxO1). Leaders in the field of PAH research are excited about the notion that addressing master transcription factors may integrate the metabolic and inflammatory theories behind PAH, as a single target would simplify the goal of PAH treatment. Simply put, one therapy could someday address metabolic and inflammatory issues associated with the disease. One group at the University of Alberta in Edmonton, Canada, believes that targeting FoxO1 may help improve bench-to-bedside drug translation, although there are many facets of disease that must be understood before this ideal is realized.

“Targeting more proximal hubs that integrate many mechanisms in the PAH pathogenesis cascade will be more effective that attacking individual distal targets,” wrote Dr. Roxane Paulin, lead author of “Addressing Complexity in Pulmonary Hypertension: The FoxO1 Case,” which was published in Circulation Research as a commentary on cutting edge science. Although many FoxO proteins serve as transcription factors for integrating cellular signals, FoxO1 is associated with multiple signals in PAH.

Primarily, FoxO1 is an active protein during inflammation, which is increasingly recognized as playing a role in PAH. FoxO1 serves to promote T-cell quiescence and reduce inflammation, while depleting FoxO1 spontaneously activates T cells and increases inflammation. Signaling mediates the switch between quiescent and activated T-cells, and FoxO1 relocates from the nucleus into the cytosol. Understanding the location of proteins inside cells is essential for designing therapies that target those proteins.

Just as important, FoxO1 is a key regulator of metabolic processes. “Metabolism is a critical driver of PAH pathogenesis,” stated Dr. Paulin. In PAH, lung and other tissues are affected by mitochondrial suppression. This induces an increased uptake of glucose by cells. As FoxO1 is progluconeogenic, inhibiting its action results in a phenotype similar to PAH. This fact has elicited investigations in activating FoxO1 in cardiomyocytes, but progress in these studies has been slow.

One barrier to using FoxO1 activators in the management of PAH is the ubiquity of FoxO1 in unrelated signaling pathways. Studies that use nucleus-excluding stimuli (FoxO1 is active in the cytosol) result in unexpected adverse effects, preventing further studies with these stimulators. FoxO1 activity also represses endothelial nitric oxide synthase, which is another key protein involved in managing PAH through vasodilation effects. This exemplifies how, although a common hub of PAH pathogenesis is attractive from a treatment standpoint, affecting a protein involved in numerous signaling pathways must be carefully studied.