Elevated microRNA-187 causes cardiac endothelial dysplasia to promote congenital heart disease through inhibition of NIPBL
Chao Li, … , Jianfeng Shen, Hongyan Wang
Chao Li, … , Jianfeng Shen, Hongyan Wang
Published November 25, 2024
Citation Information: J Clin Invest. 2025;135(1):e178355. https://doi.org/10.1172/JCI178355.
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Research Article Cardiology Development

Elevated microRNA-187 causes cardiac endothelial dysplasia to promote congenital heart disease through inhibition of NIPBL

Abstract

Cardiac endothelial cells are essential for heart development, and disruption of this process can lead to congenital heart disease (CHD). However, how microRNAs influence cardiac endothelial cells in CHD remains unclear. This study identified elevated microRNA-187 (miR-187) expression in embryonic heart endothelial cells from CHD fetuses. Using a conditional knockin model, we showed that increased miR-187 levels in embryonic endothelial cells induce CHD in homozygous fetal mice, closely mirroring human CHD. Mechanistically, miR-187 targets NIPBL, which is responsible for recruiting the cohesin complex and facilitating chromatin accessibility. Consequently, the endothelial cell–specific upregulation of miR-187 inhibited NIPBL, leading to reduced chromatin accessibility and impaired gene expression, which hindered endothelial cell development and ultimately caused heart septal defects and reduced heart size both in vitro and in vivo. Importantly, exogenous miR-187 expression in human cardiac organoids mimicked developmental defects in the cardiac endothelial cells, and this was reversible by NIPBL replenishment. Our findings establish the miR-187/NIPBL axis as a potent regulator that inhibits cardiac endothelial cell development by attenuating the transcription of numerous endothelial genes, with our mouse and human cardiac organoid models effectively replicating severe defects from minor perturbations. This discovery suggests that targeting the miR-187/NIPBL pathway could offer a promising therapeutic approach for CHD.

Authors

Chao Li, Zizheng Tan, Hongdou Li, Xiaoying Yao, Chuyue Peng, Yue Qi, Bo Wu, Tongjin Zhao, Chentao Li, Jianfeng Shen, Hongyan Wang

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Figure 6

MiR-187 reduces endocardial gene expression and chromatin accessibility and inhibits endothelial cell migration and tube formation.

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MiR-187 reduces endocardial gene expression and chromatin accessibility ...
(A) Heatmap of RNA-Seq analyses of expression levels of 208 core genes represented in Gene Ontology (GO) terms of GSEA, involved in endothelial cell migration, proliferation, differentiation, vascular endothelial growth factor (VEGF) signaling pathway, mesenchymal cell differentiation, heart morphogenesis, and cardiac septum development for miR-NC–hESC-ECs, miR-187–hESC-ECs, and miR-187/NIPBL–hESC-ECs. (B) Schematic illustration of the screening approach for downstream genes of miR-187/NIPBL axis using NIPBL, H3K27Ac CUT&TAG-seq and miR-NC–hESC-EC, miR-187–hESC-EC, and miR-187/NIPBL–hESC-EC RNA-Seq. (C) Heatmap of RNA-Seq analyses of 29 screened genes for miR-NC–hESC-ECs, miR-187–hESC-ECs, and miR-187/NIPBL–hESC-ECs. (D) RT-qPCR analysis of 29 screened genes in endocardial cells of WT and miR-187–KI mice (n = 4). GAPDH was used as an internal control. (E and F) Genome Browser displays representative views of ATAC-seq and RNA-Seq signals for the indicated genes (left), while ATAC-qPCR quantification shows the chromatin accessibility of these genes (n = 4) (right), comparing hESC-ECs with miR-NC, miR-187, miR-187+NIPBL (E), as well as mice with +/+ and KI/KI genotypes (F). (G) Schematic diagram of the role of the miR-187/NIPBL axis in the pathogenesis of CHD. Data are shown as means ± SD. ns, P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001. Significance was determined by 1-way ANOVA (D–F).