The Role of miR-100–5p in Fibroelastic Remodeling

All articles of this category (opens in new window) Background: Hemodynamic alterations induce fibroelastic remodeling of the endocardium in hypoplastic left heart syndrome (HLHS) through endothelial-to-mesenchymal transition (EndMT). MicroRNAs are known regulators of epithelial-to-mesenchymal transition in cancer, but their role in EndMT-driven cardiac fibrosis remains unclear. Previous work from our group identified miR-100–5p as upregulated in endocardial tissue and in endocardial fibroelastosis-derived endocardial endothelial cells (EdEECs) from HLHS patients, suggesting regulation of TGF-β signaling via its targets SKI, ZBTB7A, and CYP26B1. We therefore investigated whether pathological shear stress induces miR-100–5p expression and its downstream targets in EdEECs. Methods: Human healthy endocardial endothelial cells (HEECs) were exposed to physiological shear stress and EdEECs ( n = 3/group) to pathological shear stress for 6 hours using ibidi chambers mimicking the human condition. Expression of miR-100–5p, SKI, ZBTB7A, and CYP26B1 was quantified by qRT-PCR. Conditioned media were analyzed for miR-100–5p release. Results: Pathological shear stress induced a significant upregulation of miR-100–5p in EdEECs compared with HEECs ( p < 0.0473). SKI expression was significantly decreased in EdEECs exposed to pathological shear stress ( p < 0.0009), whereas ZBTB7A remained unchanged ( p = 0.891). For CYP26B1, there was a trend toward downregulation under high shear stress, although this did not reach statistical significance due to the small sample size compared with healthy cells under physiological shear stress. Additionally, miR-100–5p was detectable in conditioned media of shear-exposed cells, indicating extracellular release. Conclusion: Our data provide the first evidence that pathological shear stress induces upregulation of miR-100–5p in endocardial fibroelastosis-derived endocardial endothelial cells, with downregulation of SKI, a negative regulator of TGF-β signaling, as well as a trend toward downregulation of CYP26B1, a key regulator of early heart development. In contrast, the unchanged expression of ZBTB7A, another negative regulator of TGF-β signaling, may reflect early translational repression rather than mRNA decay. Collectively, these findings support a role for miR-100–5p as a regulator of EndMT and highlight its potential as a biomarker of developing endocardial fibroelastic remodeling in patients with HLHS. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany