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 3

Endothelial cell–specific expression of exogenous miR-187 drives CHD.

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Endothelial cell–specific expression of exogenous miR-187 drives CHD. (A...
(A) RT-qPCR analysis of mmu-miR-187 levels in the hearts, endothelial cells, cardiomyocytes, and other tissues excluding CD31-positive cells (kidneys, brains, and lungs) of P0 neonatal mice with the indicated genotypes (n = 6). (B) Stereoscopic images of whole hearts from homozygous, heterozygous miR-187–KI, and control mice at P0. (C–E) Body weight (C), heart weight/body weight ratio (D), and heart weight (E) of P0.5 neonatal homozygous miR-187–KI and control mice (n = 24). (F–H) Echocardiographic assessment of representative M-mode images of the left ventricle (F), ejection fraction (EF) (G), and systolic intraventricular septum (IVS s) (H) in control mice and miR-187–KI mice (n = 8). (I) Quantification of cardiac defect number according to stereoscopic images and H&E-stained sections of whole hearts of control mice and homozygous miR-187–KI mice. (J–L) H&E-stained heart sections from homozygous miR-187–KI and control mice, displaying human-CHD-like phenotypes; for example, the control heart shows a normal septum (J), and a miR-187–KI littermate of the animal in K and L shows VSD (K, arrow) and aorta overriding (L, arrow) at P0.5. (M) Quantification of the intensity mean value of CD31 (red) per field of view (n = 5). (N) FACS analysis and quantification of CTNT and CD31-positive cells from homozygous, heterozygous miR-187–KI, and control mice at P0.5 (n = 8). Scale bars: 1,000 μm (B), 200 μm (J–L), 5 μm (M). Data are shown as means ± SD. ns, P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Significance was determined by 1-way ANOVA (A, C–E, G, H, M, and N) and Pearson’s χ2 test (I).