Long non‐coding RNAs influence the transcriptome in pulmonary arterial hypertension: the role of PAXIP1‐AS1

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.

Basement Membrane Remodeling Controls Endothelial Function in Idiopathic Pulmonary Arterial Hypertension

“…Experiments were adapted as previously described (17). In brief, 10,000 hPAECs (per well in quadruplicates) were seeded on 96-well plates precoated with indicated substrates in EGM-2 full media and allowed to adhere for 40 minutes at 37 8 (18). Primers are found in Table 2.…”

Endothelial Basement Membrane Components and Their Products, Matrikines: Active Drivers of Pulmonary Hypertension?

“…By direct binding to integrin α5β1 and caveolin-1 [129,164] and inhibition of VEGF effects as an antagonist on VEGFR2 (KDR/Flk) [130], endostatin disrupts the cytoskeletal rearrangement and the focal adhesion complex via the inhibition of paxillin and FAK phosphorylation [185]. Both paxillin and FAK signaling at the focal adhesion machinery are involved in mediating some of the phenotypic alteration in pulmonary arterial smooth muscle cell behavior in PAH, such as hyperproliferation, migration, and apoptosis resistance [186][187][188][189].…”

Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease

“…Similarly, hypoxia promotes the expression of lncRNA PAXIP1-AS1. PAXIP1-AS1 alters the focal adhesion signaling and upregulates paxillin, which leads to increased proliferation and migration of PASMCs (176). Another hypoxia-induced lncRNA is UCA1 (urothelial carcinoma-associated-1).…”