MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

Abstract

Background Pulmonary arterial hypertension (PAH) is characterized by the apoptosis resistance and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Its pathogenesis has not been revealed. Here, we carried out experiments to investigate the functions of miR‐140‐5p and tumor necrosis factor‐α (TNF‐α). Methods We selected GSE703 from Gene Expression Omnibus (GEO) Database to conduct microarray analysis using R software and Gene Set Enrichment Analysis (GSEA). Combing bioinformatics results, the upregulation of miR‐140‐5p inhibited PAH progression through targeting TNF‐α. RNA expression was measured by quantitative real‐time polymerase chain reaction (RT‐qPCR) and protein level was measured by western blot analysis and enzyme‐linked immunosorbent assays (ELISA). We conducted monocrotaline (MCT) injection to rats to form PAH animal models. The lung tissues were observed by hematoxylin–eosin (HE) staining and Sirius red‐picric acid staining. Right ventricular systolic pressure (RVSP) and the ratio of right ventricle (RV)‐to‐left ventricle (LV) plus septum (S) weight (RV/[LV + S]) were measured in MCT‐induced animal models. Overexpression of miR‐140‐5p and TNF‐α were utilized to research the proliferation, migration, and phenotypic variation of hypoxia‐mediated PASMCs. The binding between miR‐140‐5p and TNF‐α 3′‐untranslated region (3′‐UTR) was confirmed via luciferase reporter assay. Results Downregulation of miR‐140‐5p and upregulation of TNF‐α were observed in PAH rat model and hypoxia‐mediated PASMCs. And we proved that overexpression of miR‐140‐5p could suppress the proliferation, migration, and phenotypic variation of PASMCs, therefore inhibiting PAH pathogenesis. Luciferase assay verified that miR‐140‐5p targeted TNF‐α directly. A converse correlation was also shown between miR‐140‐5p and TNF‐α in PASMCs. Conclusions miR‐140‐5p and TNF‐α are important regulators in PAH pathology and may serve as a therapeutic target for PAH.

Noncoding RNAs in Hypertension

“…Downregulation of miR-140-5p and upregulation of TNF-α (tumor necrosis factor-α) may induce pathological events in PAHT. 70…”

LncRNA‐GAS5 related to the processes of recurrent pregnancy loss by regulating Th1/Th2 balance

“…MiR-140-5p has been found to be an immune response inhibitor in patients with acute lung injury, osteoarthritis and pulmonary arterial hypertension. [36][37][38] It is reported that miR-140-5p directly target TNF-α and repressed its expression in pulmonary artery smooth muscle cells. 36 In the present study, we confirmed that miR-140-5p also repressed TNF-α in trophoblasts.…”

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