Roles of LncRNAs in the Pathogenesis of Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a persistently progressive, incurable, multifactorial associated fatal pulmonary vascular disease characterized by pulmonary vascular remodeling. Long noncoding RNAs (lncRNAs) are involved in regulating pathological processes such as pulmonary vasoconstriction, thickening, remodeling, and inflammatory cell infiltration in PH by acting on different cell types. Because of their differential expression in PH patients, as demonstrated by the observation that some lncRNAs are significantly upregulated while others are significantly downregulated in PH patients, lncRNAs are potentially useful biomarkers for assessing disease progression and diagnosis or prognosis in PH patients. This article provides an overview of the different mechanisms by which lncRNAs are involved in the pathogenesis of PH.

Keywords: inflammatory and immune responses; long noncoding RNAs; pulmonary adventitial fibroblasts; pulmonary arterial endothelial cells; pulmonary artery smooth muscle cells; pulmonary hypertension; right ventricle; vascular remodeling.

Fig. 1.

Methods for studying lncRNAs. ZNF, zinc-finger nuclease; TALEN, transcription activator like effector nuclease; PARS, RNA antisense purification; PARIS, psoralen analysis of RNA interactions and structures; SHAPE, selective $2^{\prime }$-hydroxylacylation analyzed by primer extension; DMS-Seq, dimethyl dulfate sequencing; c-KLAN, combined knockdown and localization analysis of noncoding RNAs; RNA-Fish, RNA fluorescence in situ hybridization; RNA-Seq, RNA sequencing; CAGE, cap analysis of gene expression; SAGE, serial analysis of gene expression; SPR, surface plasmon resonance; RAP-MS, RNA antisense purification with mass spectrometry; EMSA, electrophoretic mobility shift assay; CLIP, cross-linking immunoprecipitation; CLIP-Seq, cross-linking immunoprecipitation sequencing; PAR CLIP, photoactivable ribonucleoside enhanced CLIP; HITS CLIP, high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation; iCLIP, individual-nucleotide resolution CLIP; eCLIP, enhanced CLIP; CLASH, crosslinking-ligation and sequencing ofhybrids; RAP, RNA antisense purification; RAP-Seq, RNA antisense purification sequencing; dCHIRP, domain-specifi chromatin isolation by RNA purification; CHART, capture hybridization analysis of RNA targets; TRAP, tagged RNA affinity purification; 3C, chromosome conformation capture; 4C, circular chromosome conformation capture; 5C, chromosome conformation capture carbon copy; lncRNAs, long noncoding RNAs; siRNA, small interfering RNA; shRNA, short hairpin RNA; esiRNA, endogenous small interfering RNAs; MPSS, massively parallel signature sequencing.

Fig. 2.

LncRNAs act on PH through different mechanisms. MALAT1, metastasis-associated lung adenocarcinoma transcript 1; TUG1, taurine-upregulated gene 1; MEG3, maternally expressed gene 3; SMILR, smooth muscle enriched long noncoding RNA; NEAT1, nuclear paraspeckle assembly transcript 1; PVT1, plasmocytoma variant translocation 1; CASC2, cancer susceptibility candidate gene 2; Gas5, growth arrest-specific 5; PAHRF, pulmonary arterial hypertension related factor; lnc-Ang362, lncRNA 362 regulated by angiotensin II; TYKRIL, tyrosine kinase recemtor inducing lncRNA; PAXIP1-AS1, PAXIP1 antisense RNA 1; CPS1-IT, CPS1 intron transcript 1; HOXA-AS3, HOXA cluster antisense RNA 3; LncPTSR, lncRNA neighboring the locus of ATPase plasma membrane ${\mathrm{Ca}}^{2+}$ $\beta$; Rps4l, lncRNA ribosomal protein S4-like; PH, pulmonary hypertension; MIAT, myocardial infarction-associated transcripts; LncRNAs, Long noncoding RNAs; SOX2-OT, lncRNA SOX2-overlapping transcript; LINC00963, long intergenic non-protein coding RNA 963; miRNA, microRNA; GATA6-AS, GATA6 antisense RNA 1; LnRPT, lncRNA regulated by PDGF and transforming growth factor $\beta$; mRNA, message RNA; HAS2-AS1, hyaluronan synthase 2 antisense 1.