Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH.

Forkhead Box Protein O1 is Linked to Anti-Inflammatory Probiotic Bacteria Acting through Nuclear Factor-κB Pathway

“…Different responses to TNFα were observed for FoxO1 in diverse models, for instance, treatment of pulmonary artery smooth muscle cells with TNFα produce down regulation of FoxO1; in bone marrow derived mesenchymal stem cells TNFα also inhibits FoxO1. Nevertheless, in adipocytes and fibroblasts the treatment with TNFα activates FoxO1 [37][38][39]. Our observations are aligned with previous findings that show an activation of AKT pathway in response to TNFα in HT-29 cells.…”

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

“…Indeed, the conservation of an abnormal cellular phenotype outside their natural habitats has been demonstrated for primary cultures at early passages. In severe PAH, PAECs and PASMCs exhibit hyperproliferative and apoptosis-resistant phenotypes contributing to the extensive pulmonary vascular remodeling observed in PAH (27)(28)(29)(30)(31)(32), as well as proinflammatory phenotypes (33,34).…”

Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

“…BMPR-II agonists and drugs that non-specifically enhance BMP signalling have shown beneficial effects in experimental PH [24,[28][29][30][31]. In cultured ECs, BMP9 was shown to increase BMPR-II signalling, prevent apoptosis, decrease angiogenic behaviour and promote monolayer integrity [31].…”