Dataset Information

MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension.

ABSTRACT: Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH.

SUBMITTER: Rothman AM

PROVIDER: S-EPMC4922709 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension.

Rothman Alexander M K AM Arnold Nadine D ND Pickworth Josephine A JA Iremonger James J Ciuclan Loredana L Allen Robert M H RM Guth-Gundel Sabine S Southwood Mark M Morrell Nicholas W NW Thomas Matthew M Francis Sheila E SE Rowlands David J DJ Lawrie Allan A

The Journal of clinical investigation 20160523 7

Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. ...[more]

PMID: 27214554

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Project description:BackgroundThe role of microRNAs (miRNAs) in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) remains to be fully elucidated. This study evaluated the expression profile of miRNAs in the lung tissue of patients with SSc-PAH.MethodsLung tissue samples were collected from 3 SSc-PAH patients and 4 healthy controls. A small RNA high throughput sequence approach was used for screening the differentially expressed miRNAs in the lung tissue samples. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate 4 highly significant differentially expressed miRNAs. Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for mRNAs were performed using the R package clusterProfiler software.ResultsA total of 82 upregulated miRNAs and 35 downregulated miRNAs were detected in the lung tissues of patients with SSc-PAH compared with healthy controls. GO enrichment analysis demonstrated that the upregulated target genes were closely involved in biological processes such as nervous system development, anatomical structure morphogenesis, system development, cellular macromolecule metabolic processes, and cellular processes. The downregulated target genes were involved in the plasma membrane bound cell projection morphogenesis and the regulation of macromolecule metabolic processes. The KEGG enrichment analysis showed that the upregulated genes were associated with important pathways involved in cancer biology, and the target genes of the downregulated miRNAs were involved in axon guidance. High throughput sequencing and qRT-PCR revealed that hsa-miR-205-5p and hsa-miR-539-3p were differentially expressed in SSc-PAH tissue. The target genes of hsa-miR-205-5p and hsa-miR-539-3p, IRF1and ADCYAP1, respectively, were verified using the high throughput dataset GSE48149.ConclusionsmiRNAs may play an important role in the pathogenesis of SSc-PAH, and hsa-miR-205-5p and hsa-miR-539-3p may be potential therapeutic targets in patients with SSc-PAH.

Project description:MicroRNAs (miRNAs) are versatile regulators of pulmonary arterial remodeling in idiopathic pulmonary arterial hypertension (IPAH). We herein aimed to characterize miRNAs in peripheral blood mononuclear cell (PBMC) and plasma exosomes, and investigate specific miRNA expression in pulmonary artery cells and lung tissues in IPAH. A co-dysregulated miRNA was identified from the miRNA expression profiles of PBMC and plasma exosomes in IPAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the potential function of differentially expressed miRNAs. Real-time quantitative reverse transcription polymerase chain reaction was used to validate the expression of specific miRNAs in hypoxia-induced pulmonary microvascular endothelial cells (PMECs), pulmonary artery smooth muscle cells (PASMCs), pericyte cells (PCs), and lung tissues of patients with IPAH and rats. Finally, the miRNA-mRNA mechanisms of miR-122-5p were predicted. MiR-122-5p was the only co-upregulated miRNA in PBMC and plasma exosomes in patients with IPAH. Functional analysis of differentially expressed miRNAs revealed associations with the GO terms "transcription, DNA-templated," "cytoplasm," and "metal ion binding" in both PBMC and plasma exosomes, KEGG pathway MAPK signaling in PBMC, and KEGG-pathway human papillomavirus infection in plasma exosomes. Hypoxic PMECs and PCs, lung tissue of patients with IPAH, and rats showed increased expression of miR-122-5p, but hypoxic PASMCs showed decreased expression. And miR-122-5p mimics and inhibitor affected cell proliferation. Finally, miR-122-5p was found to potentially target DLAT (in lung tissue) and RIMS1 (in PMECs) in IPAH. According to the dual-luciferase assay, miR-122-5p bound to DLAT or RIMS1. In studies, DLAT imbalance was associated with cell proliferation and migration, RIMS1 is differentially expressed in cancer and correlated with cancer prognosis. Our findings suggest that the miR-122-5p is involved in various biological functions in the adjacent vascular wall cells in IPAH.

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MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension.

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MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension.

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