Fig. 3: The role of hippo signaling pathway in PAH.

Inactivation of LATS1 enhanced the activity of YAP. YAP promotes the transcription of Pik3cb, which encodes the catalytic subunit P110β of PI3K and enhances TEAD, thereby activating the PI3K/AKT pathway. PI3K/AKT pathway promotes PAVSMCs proliferation and pulmonary vascular remodeling and aggravates PAH. In addition, inactivation of LATS1 leads to LATS1-YAP dysregulation, which promotes the production of fibronectin and activates ILK1. Inhibition of ILK reactivating LATS1 in PAVSMCs leads to downregulation of YAP, inhibition of PAVSMCs proliferation, and induction of apoptosis. In addition, S1P promotes the activation of STAT3 through S1PR2 or autocrine loop signaling, which further lead to STAT3 translocates to the nucleus [97, 108]. STAT3 translocation further reduces the expression of E3 ubiquitin ligase β -transduction repeat protein and inhibits degradation of YAP ubiquitination in PAVSMCs. Note: PAH pulmonary arterial hypertension, LATS1/2 large tumor suppressor 1/2, TEAD TEA domain family, S1P sphingosine-1-phosphate, PAVSMCs pulmonary arterial vascular smooth muscle cells, S1PR2 sphingosine-1-phosphate receptor 2, ILK1 integrin-linked kinase 1, PI3K phosphatidylinositol 3-kinase.