LncRNA PAXIP1‐AS1 fosters the pathogenesis of pulmonary arterial hypertension via ETS1/WIPF1/RhoA axis

• Published in: Journal of cellular and molecular medicine Vol. 25; no. 15; pp. 7321 - 7334
• Main Authors: Song, Rong, Lei, Si, Yang, Song, Wu, Shang‐Jie
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2021; John Wiley and Sons Inc
• Subjects: Animals; Cancer; Cell adhesion & migration; Cell growth; Cell migration; Cell proliferation; Cell viability; Cells, Cultured; Cholecystokinin; Cytoskeletal Proteins - metabolism; DNA-Binding Proteins - genetics; Ets-1 protein; ETS1; Humans; Hypertension; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypoxia; Immunofluorescence; Immunohistochemistry; Immunoprecipitation; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lung diseases; Male; Monocrotaline; Muscle, Smooth, Vascular - metabolism; Original; Pathogenesis; PAXIP1‐AS1; Plasmids; Proto-Oncogene Protein c-ets-1 - metabolism; Pulmonary arterial hypertension; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - metabolism; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; RhoA; rhoA GTP-Binding Protein - metabolism; RhoA protein; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Smooth muscle; Transcriptomes; Veins & arteries; Western blotting; WIPF1; Wound healing; United States > US; China; Japan; Germany; PAXIP1-AS1; Pulmonary arterial hypertension; WIPF1; ETS1; RhoA
• DOI: 10.1111/jcmm.16761
• ISSN: 1582-1838

Pulmonary arterial hypertension (PAH) is a life‐threatening disease featured with elevated pulmonary vascular resistance and progressive pulmonary vascular remodelling. It has been demonstrated that lncRNA PAXIP1‐AS1 could influence the transcriptome in PAH. However, the exact molecular mechanism of PAXIP1‐AS1 in PAH pathogenesis remains largely unknown. In this study, in vivo rat PAH model was established by monocrotaline (MCT) induction and hypoxia was used to induce in vitro PAH model using human pulmonary artery smooth muscle cells (hPASMCs). Histological examinations including H&E, Masson's trichrome staining and immunohistochemistry were subjected to evaluate the pathological changes of lung tissues. Expression patterns of PAXIP1‐AS1 and RhoA were assessed using qRT‐PCR and Western blotting, respectively. CCK‐8, BrdU assay and immunofluorescence of Ki67 were performed to measure the cell proliferation. Wound healing and transwell assays were employed to evaluate the capacity of cell migration. Dual‐luciferase reporter assay, co‐immunoprecipitation, RIP and CHIP assays were employed to verify the PAXIP1‐AS1/ETS1/WIPF1/RhoA regulatory network. It was found that the expression of PAXIP1‐AS1 and RhoA was remarkably higher in both lung tissues and serum of MCT‐induced PAH rats, as well as in hypoxia‐induced hPASMCs. PAXIP1‐AS1 knockdown remarkably suppressed hypoxia‐induced cell viability and migration of hPASMCs. PAXIP1‐AS1 positively regulated WIPF1 via recruiting transcriptional factor ETS1, of which knockdown reversed PAXIP1‐AS1‐mediated biological functions. Co‐immunoprecipitation validated the WIPF1/RhoA interaction. In vivo experiments further revealed the role of PAXIP1‐AS1 in PAH pathogenesis. In summary, lncRNA PAXIP1‐AS1 promoted cell viability and migration of hPASMCs via ETS1/WIPF1/RhoA, which might provide a potential therapeutic target for PAH treatment.