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.
Highlights
Pulmonary arterial hypertension (PAH) is a severe and progressive disease which leads to right heart failure [1]
We focus on the functional role of a highly deregulated Long non-coding RNAs (lncRNAs), PAXIP1-AS1, in perpetuating the migratory and proliferative phenotype of idiopathic pulmonary arterial hypertension (IPAH) pulmonary artery smooth muscle cells (PASMCs)
Based on a minimum significance (–log10 p) of 3 and a minimum absolute log2 fold change (LFC) of 1.25, 124 annotated protein-coding genes were classified as up- (76) or down-regulated (48) in IPAH compared with control donor samples (Figure 1A and supplementary material, Table S1)
Summary
Pulmonary arterial hypertension (PAH) is a severe and progressive disease which leads to right heart failure [1]. Multiple factors contribute to the increased pulmonary pressure, including cellular hyperplasia and extracellular matrix (ECM) deposition [2,3]. Smooth muscle cells (SMCs) show increased proliferation [4], invasive migratory capacity, and resistance to apoptosis [5]. These functional alterations are accompanied by a reprogramming of cellular respiration [6] and glucose expenditure [7]. PAH has a strong genetic predisposition, with several mutations contributing to the disease development [8]. Loss-of-function mutations in BMPR2 occur in over 70% of patients with familial PAH and in 25% of patients with the idiopathic form [9]. It is apparent that additional regulatory mechanisms are involved and factors other than solely mutations in coding genes are required for disease development
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