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Circulating miRNA analysis in Pulmonary Arterial Hypertension patients, overexpression of miR-3168 downregulates BMPR2 and impairs angiogenesis in vitro

ABSTRACT: Pulmonary Arterial Hypertension (PAH) is a rare disease where the thickening of the precapillary pulmonary arteries ends up inducing right heart failure. Nowadays, getting an early diagnosis is complicated and usually delayed until performing right-heart catheterization. In this work, we performed small RNA sequencing in the plasma of idiopathic PAH patients and controls. We were able to find 29 differentially expressed microRNAs and validate 7 of them in a nationwide cohort (let-7a-5p, let-7b-5p, let-7c-5p, let-7f-5p, miR-9-5p, miR-31-5p, miR-3168). We then used classification models to analyze their potential as PAH predictors. In the first half of our cohort, we obtained a model with an AUC of 0.888. Although, this value lowered to 0.738 after using this model in the whole cohort of patients. Also, we validated the effect of miR-3168, a novel upregulated miRNA in PAH patients that targets the BMPR2 and impairs angiogenesis as measured in tube formation assay. In conclusion, we found novel downregulated and upregulated microRNAs in idiopathic PAH patients. We developed a 3-microRNA signature for diagnosis and validated in vitro that miR-3168 targets BMPR2 and impairs angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222022 | GEO | 2024/03/31

REPOSITORIES: GEO

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Project description:Pulmonary arterial hypertension (PAH) is a progressive disorder leading to occlusive vascular remodeling. Current PAH therapies improve quality of life but do not reverse structural abnormalities in the pulmonary vasculature. Here, we used a high-throughput drug screen combined with in silico analyses of existing transcriptomic datasets to identify a promising lead compound to reverse PAH. Induced pluripotent stem cell-derived endothelial cells (iPSC-EC) generated from six patients with PAH were exposed to 4,500 compounds and assayed for improved cell survival after serum withdrawal using a chemiluminescent caspase assay. Subsequent validation of caspase activity and improved angiogenesis combined with in silico analyses using the Gene Expression Omnibus (GEO ) and Library of Integrated Network-Based Cellular Signatures (LINCS) databases revealed that the lead compound AG1296 was positively associated with an anti-PAH gene signature. AG1296 increased abundance of bone morphogenetic protein receptors (BMPR2 and Ia), downstream signaling and gene expression, and suppressed PAH smooth muscle cell proliferation. AG1296 induced regression of pulmonary arterial (PA) neointimal lesions in lung organ culture and PA occlusive changes in the Sugen/hypoxia rat model and reduced right ventricular systolic pressure. Moreover, AG1296 improved vascular function and BMPR2 signaling and showed better correlation with the anti-PAH gene signature than other tyrosine kinase inhibitors (TKIs) such as imatinib. Specifically, AG1296 upregulated the transcription factors and small mothers against decapentaplegic (SMAD)1/5 co-activators, cAMP-response element binding protein (CREB)3 and CREB5: CREB3 induced inhibitor of DNA binding 1 (ID1) and downstream genes that improved vascular function. Thus, drug discovery for PAH can be accelerated by combining a phenotypic screen using patient-specific iPSC-derived vascular cells with in silico analyses of publicly available datasets.

Dataset Information

Circulating miRNA analysis in Pulmonary Arterial Hypertension patients, overexpression of miR-3168 downregulates BMPR2 and impairs angiogenesis in vitro

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