July 2020

Am J Respir Crit Care Med

Long Noncoding RNA TYKRIL Plays a Role in Pulmonary Hypertension via the p53-Mediated Regulation of PDGFRbeta

Zehendner CM, Valasarajan C, Werner A, Boeckel JN, Bischoff FC, John D, Weirick T, Glaser SF, Rossbach O, Jae N, Demolli S, Khassafi F, Yuan K, De Jesus Perez VA, Michalik KM, Chen W, Seeger W, Guenther A, Wasnick RM, Uchida S, Zeiher AM, Dimmeler S, Pullamsetti SS.



Rationale: Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored.

Objectives: To elucidate the role of tyrosine kinase receptor inducing lncRNA (TYKRIL) as a regulator of p53/platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and to investigate its role in PAH.

Measurements and main results: 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 PDGFRβ, a key player in PH, was found to strongly correlate with TYKRIL expression in the patient samples (n=12) and TYKRIL knockdown decreased PDGFRβ expression (n=3). Importantly, TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRβ by binding to the N-terminal of p53 and interfering with p53-p300 interaction that subsequently regulates p53 nuclear translocation.

Conclusion: TYKRIL plays an important role in PAH by regulating the p53/PDGFRβ axis.

Keywords: Long noncoding RNAs; Pericytes, smooth muscle cells; Vascular Remodeling; human Precision Cut Lung Slices; platelet-derived growth factor receptor β.