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

Abstract

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.

• Authors: Rong Song, Si Lei, Song Yang, Shang-Jie Wu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 15 Pg. 7321-7334 (08 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 34245091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Cytoskeletal Proteins
• DNA-Binding Proteins
• ETS1 protein, human
• Intracellular Signaling Peptides and Proteins
• PAXIP1 protein, human
• Proto-Oncogene Protein c-ets-1
• RNA, Long Noncoding
• WIPF1 protein, human
• RHOA protein, human
• rhoA GTP-Binding Protein

Topics

• Animals
• Cells, Cultured
• Cytoskeletal Proteins (metabolism)
• DNA-Binding Proteins (genetics)
• Humans
• Hypertension, Pulmonary (genetics, metabolism, pathology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Muscle, Smooth, Vascular (metabolism)
• Proto-Oncogene Protein c-ets-1 (metabolism)
• Pulmonary Artery (metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• rhoA GTP-Binding Protein (metabolism)