Inhaltspezifische Aktionen


FOXO transcription factors in PH: critical integrators of multiple immune signaling pathways driving pulmonary vascular and right ventricular remodeling

We previously provided strong evidence for the involvement of Forkhead box O (FoxO) transcription factors in pulmonary arterial hypertension (PAH=group 1 PH) pathogenesis. Post-transcriptional and post-translational modifications of FoxO factors can alter their subcellular localization and activity with repercussions on the adaptability to mechanical and metabolic stress of different cell types. Importantly, lack of FoxO1 in pulmonary artery smooth muscle cells (PASMCs) resulted in reduced chromatin accessibility and decreased transcriptional activity at the promoter regions of several putative FoxO1 target genes, which are mainly involved in immune function and inflammation. Intriguingly, FoxO1 deficiency in PASMCs mimicked the effect of hypoxia exposure at the transcriptional level by inducing angiogenetic genes and at the same time inhibiting expression of immune function genes. These data indicate a possible protective role of FoxO factors against hypoxia-induced vascular remodeling via modulation of the immune function. Interestingly, infiltrating T cells have been associated with initiation and exacerbation of PAH in rodent models as well as in patients, suggesting that immune cells may drive remodeling of PASMCs. FoxO1 is a regulator of T cell differentiation into specific populations involved directly in PAH, such as Treg cells and Th9 cells. Therefore, we will investigate the function of FoxOs in T cells in the context of PAH. Against this background the future project will focus on: 1) studying the roles of FoxOs and ADAR1 in different Th cell populations under hypoxia, 2) investigating the roles of T cell specific FoxO and ADAR pathways in PAH development and RV dysfunction, 3) investigating the role of distinct immune and Th cell subpopulations in PAH and RV dysfunction.