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Long non‐coding RNAs influence the transcriptome in pulmonary arterial hypertension: the role of PAXIP1‐AS1
Author(s) -
Jandl Katharina,
Thekkekara Puthenparampil Helene,
Marsh Leigh M,
Hoffmann Julia,
Wilhelm Jochen,
Veith Christine,
Sinn Katharina,
Klepetko Walter,
Olschewski Horst,
Olschewski Andrea,
Brock Matthias,
Kwapiszewska Grazyna
Publication year - 2019
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5195
Subject(s) - transcriptome , biology , phenotype , microbiology and biotechnology , transcriptional regulation , long non coding rna , cell , myocyte , gene expression profiling , cancer research , bioinformatics , gene expression , downregulation and upregulation , gene , genetics
Abstract In idiopathic pulmonary arterial hypertension (IPAH), global transcriptional changes induce a smooth muscle cell phenotype characterised by excessive proliferation, migration, and apoptosis resistance. Long non‐coding RNAs (lncRNAs) are key regulators of cellular function. Using a compartment‐specific transcriptional profiling approach, we sought to investigate the link between transcriptional reprogramming by lncRNAs and the maladaptive smooth muscle cell phenotype in IPAH. Transcriptional profiling of small remodelled arteries from 18 IPAH patients and 17 controls revealed global perturbations in metabolic, neuronal, proliferative, and immunological processes. We demonstrated an IPAH‐specific lncRNA expression profile and identified the lncRNA PAXIP1‐AS1 as highly abundant. Comparative transcriptomic analysis and functional assays revealed an intrinsic role for PAXIP1‐AS1 in orchestrating the hyperproliferative and migratory actions of IPAH smooth muscle cells. Further, we showed that PAXIP1‐AS1 mechanistically interferes with the focal adhesion axis via regulation of expression and phosphorylation of its downstream target paxillin. Overall, we show that changes in the lncRNA transcriptome contribute to the disease‐specific transcriptional landscape in IPAH. Our results suggest that lncRNAs, such as PAXIP1‐AS1 , can modulate smooth muscle cell function by affecting multiple IPAH‐specific transcriptional programmes. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.