LncRNA Xist Participates in Signaling Pathways Related to Pulmonary Arterial Hypertension and its Comorbidities

Abstract

Population‐based studies indicate a female predominance in pulmonary arterial hypertension (PAH) of around 2 – 4 over men for all races/ethnicities and across all ages that have been studied to date. While female gender has long been established as the major clinical risk factor for PAH, other factors such as infections, autoimmune diseases, inflammation, obesity, obstructive sleep apnea and genetic predisposition have also been associated with PAH. Obstructive sleep apnea, a common comorbidity of PAH, leads to intermittent periods of apnea, significant hypoxemia, but importantly, also to hypercapnia both of which, in turn, serve to induce pulmonary arteriolar vasoconstriction and PAH. The mechanistic links between hypoxemia/hypercapnia and vascular remodeling remain unclear. Our studies sought to investigate whether obstructive sleep apnea, contributes to the severity of pulmonary artery endothelial cells (PAECs) PAH phenotype.We recently demonstrated that the increased expression and activity of the long‐noncoding (lnc)RNA‐Xist, essential for X‐chromosome inactivation and dosage compensation of X‐linked genes, drives the imbalance sex/ratio of idiopathic PAH. Using human male and female PAECs of non‐disease controls and PAH patients, in conjunction with molecular cell biology/ biochemistry, and functional approaches, we have found that the PAECs of a female specimen with PAH and obstructive sleep‐apnea displayed the highest increase in Xist expression and proliferation rate. The augmented Xist expression leads to increased expression of the X‐linked gene Elk1, a regulator of cell cycle progression in a tissue‐ and cell‐specific manner, and repression of Klf2, a key transcription factor for endothelial homeostasis and quiescence. These molecular events, more prominent in PAECs of female with PAH and comorbid obstructive sleep apnea, may account for their hyper‐proliferative phenotype. Klf2 also targets several endothelial signature genes that regulate blood pressure, angiogenesis, vascularization etc. Our studies suggest that lncRNA Xist and its signaling network participate in various pathways related to PAH and its comorbidities.