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LncRNA-536 and RNA Binding Protein RBM25 Interactions in Pulmonary Arterial Hypertension.
Mahajan, Aatish; Kumar, Ashok; Chen, Ling; Dhillon, Navneet K.
Afiliación
  • Mahajan A; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.
  • Kumar A; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.
  • Chen L; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.
  • Dhillon NK; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.
bioRxiv ; 2024 Aug 28.
Article en En | MEDLINE | ID: mdl-39253448
ABSTRACT

OBJECTIVE:

Hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the essential features of the maladaptive inward remodeling of the pulmonary arteries in pulmonary arterial hypertension (PAH). In this study, we define the mechanistic association between long-noncoding RNA ENST00000495536 (Lnc-536) and anti-proliferative HOXB13 in mediating smooth muscle hyperplasia.

METHODS:

Antisense oligonucleotide-based GapmeRs or plasmid overexpressing lnc-536 were used to evaluate the role of lnc-536 in mediating hyperproliferation of PDGF-treated or idiopathic PAH (IPAH) PASMCs. Further, we pulled down lnc536 to identify the proteins directly interacting with lnc536. The in-vivo role of lnc-536 was determined in Sugen-hypoxia and HIV-transgenic pulmonary hypertensive rats.

RESULTS:

Increased levels of lnc-536 in PDGF-treated or IPAH PASMCs promote hyperproliferative phenotype by downregulating the HOXB13 expression. Knockdown of lnc-536 in-vivo prevented increased RVSP, Fulton Index, and pulmonary vascular remodeling in Sugen-Hypoxia rats. The lncRNA-536 pull-down assay demonstrated the interactions of RNA binding protein RBM25 with SFPQ, a transcriptional regulator that has a binding motif on HOXB13 exon Further, The RNA-IP experiment using the SFPQ antibody showed direct interaction of RBM25 with SFPQ and knockdown of RBM25 resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Finally, we examined the role of lnc-536 and HOXB13 axis in the PASMCs exposed to the dual hit of HIV and a stimulant cocaine as well.

CONCLUSION:

lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to the decrease in HOXB13 expression and hyperproliferation of smooth muscle cells associated with PAH development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos