Abstract

Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored.To elucidate the role of tyrosine kinase receptor inducing lncRNA (TYKRIL) as a regulator of p53/platelet-derived growth factor receptor ß (PDGFRß) signaling pathway and to investigate its role in PAH.Using RNAseq data, TYKRIL was identified to be consistently upregulated in pericytes and pulmonary arterial smooth muscles cells (PASMCs) exposed to hypoxia and derived from IPAH patients. TYKRIL knockdown reversed the pro-proliferative (n=3) and anti-apoptotic (n=3) phenotype induced under hypoxic and IPAH conditions. Due to the poor species conservation of TYKRIL, ex-vivo studies were carried out in precision cut lung slices (PCLS) from PH patients. Knockdown of TYKRIL in PCLS decreased the vascular remodeling (n=5). The number of PCNA positive cells in the vessels were decreased and number of TUNEL positive cells in the vessels were increased in LNA treated group compared to control. Expression of PDGFRß, a key player in PH, was found to strongly correlate with TYKRIL expression in the patient samples (n=12) and TYKRIL knockdown decreased PDGFRß expression (n=3). Importantly, TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRß by binding to the N-terminal of p53 and interfering with p53-p300 interaction that subsequently regulates p53 nuclear translocation.TYKRIL plays an important role in PAH by regulating the p53/PDGFRß axis.

View details for DOI 10.1164/rccm.201910-2041OC

View details for PubMedID 32634060