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Long noncoding RNA TYKRIL plays a role in pulmonary hypertension via the p53-mediated regulation of PDGFRβ

Item Type:Article
Title:Long noncoding RNA TYKRIL plays a role in pulmonary hypertension via the p53-mediated regulation of PDGFRβ
Creators Name:Zehendner, C.M. and Valasarajan, C. and Werner, A. and Boeckel, J.N. and Bischoff, F.C. and John, D. and Weirick, T. and Glaser, S.F. and Rossbach, O. and Jaé, N. and Demolli, S. and Khassafi, F. and Yuan, K. and de Jesus Perez, V.A. and Michalik, K.M. and Chen, W. and Seeger, W. and Guenther, A. and Wasnick, R.M. and Uchida, S. and Zeiher, A.M. and Dimmeler, S. and Pullamsetti, S.S.
Abstract: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:Human Precision Cut Lung Slices, Long Noncoding RNAs, Platelet-Derived Growth Factor Receptor β, Vascular Remodeling, Pericytes, Smooth Muscle Cells
Source:American Journal of Respiratory and Critical Care Medicine
ISSN:1073-449X
Publisher:American Thoracic Society
Volume:202
Number:10
Page Range:1445-1457
Date:15 November 2020
Official Publication:https://doi.org/10.1164/rccm.201910-2041OC
PubMed:View item in PubMed

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