Details

Autor(en) / Beteiligte

• Zehendner, Christoph M
• Valasarajan, Chanil
• Thal, Serge
• Werner, Astrid
• Boeckel, Jes-Niels
• Bischoff, Florian C
• John, David
• Weirick, Tyler
• Glaser, Simone-Franziska
• Rossbach, Oliver
• Jaé, Nicolas
• Demolli, Shemsi
• Hummel, Regina
• Kreitner, Karl-Friedrich
• Möllmann, Christian
• Michalik, Katharina M
• Chen, Wei
• Seeger, Werner
• Uchida, Shizuka
• Zeiher, Andreas M
• Dimmeler, Stefanie
• Pullamsetti, Soni

Titel

Abstract 14368: Long Noncoding RNA Tykril Plays a Role in Pulmonary Hypertension by Controlling the p53 Mediated Regulation of PDGFRβ

Ist Teil von

• Circulation (New York, N.Y.), 2019-11, Vol.140 (Suppl_1 Suppl 1), p.A14368-A14368

Ort / Verlag

by the American College of Cardiology Foundation and the American Heart Association, Inc

Erscheinungsjahr

2019

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• BackgroundIn recent years, understanding the role of epigenetic regulators in disease pathogenesis has gained interest. The role of long non coding RNA (LncRNA), which functions as epigenetic regulators are still to be explored in the field of pulmonary hypertension (PH). Pathological remodeling of pulmonary vessels and elevated pulmonary pressures are the major characteristics of PH. The pro-proliferative and anti-apoptotic phenotype of various resident and non-resident cells contribute to the vessel remodeling and molecular mechanism driving this phenotype is not well understood.ResultsUsing the RNAseq data, LncRNA TYKRIL (Tyrosine kinase receptor inducing LncRNA) 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 (60%± 2 reduction vs Ctrl, P<0.001, n=3) and anti-apoptotic (52%±3 increase vs Ctrl, P<0.001, 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 (40%±3 reduction vs Ctrl, P<0.001, n=3) and number of PCNA positive cells in the vessels (47%±3 reduction vs Ctrl, P<0.01, n=3). Expression of PDGFRβ, a key player in PH, was found to strongly correlate with TYKRIL expression in the patient samples (r=0.77, n=12) and TYKRIL knockdown decreased PDGFRβ expression (1.4±0.5 FC vs Ctrl, P<0.05, n=3). From the transcription factor-screening array, it was observed that TYKRIL knock down increased the p53 activity, a known repressor of PDGFRβ. Using RNA immunoprecipitation (RIP), it was found that TYKRIL interacts with p53 (TYKRIL enrichment FC 2.7±0.3 vs Ctrl, P<0.001, n=3). RIP using various p53 mutants demonstrated that TYKRIL binds to the N-terminal of p53 (an important region for p300 interaction with p53). The proximity ligation assay reveailed that TYKRIL interferes with the p53-p300 interaction (3.5±0.5 FC vs Ctrl, P<0.001, n=3) and regulates p53 nuclear translocation.ConclusionTYKRIL plays an important role in pulmonary hypertension by regulating the p53/PDGFRβ axis.