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bioRxiv · 10.64898/2026.07.02.736228

miR-10b Mitigates Cardiac Fibrosis Associated with Aging and Myocardial Infarction via Attenuation of Lpar2 Signaling in Cardiac Fibroblasts

Nastase-Rusu, E.-G.·Marinescu-Colan, C.-I.·Neculachi, C. A.·Lupan, A.-M.·Cosman, B. P.·Publik, M. A.·Liehn, E.·Martelli, F.·Preda, M. B.·Burlacu, A.
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Abstract

A impairs post-infarction cardiac repair through dysregulated fibroblast activation and excessive extracellular matrix (ECM) deposition, yet the molecular mechanisms driving the age-associated defects remain poorly defined. Here, we show that miR-10b upregulation in cardiac fibroblasts acts as an endogenous cardioprotective response to myocardial infarction (MI), limiting adverse remodeling through suppression of Lpar2 (lysophosphatidic acid receptor 2). Using integrative analysis of mRNA and small RNA transcriptomes in cardiac fibroblasts from young and aged mice, we demonstrate that miR-10b is enriched in cardiac fibroblasts and further upregulated in experimental models of cardiac fibrosis, but not in hepatic fibrosis. Temporal profiling after MI revealed a biphasic regulation of miR-10b, with downregulation during the early inflammatory phase followed by upregulation during the reparative and maturation phases. Gain-of-function experiments in cardiac fibroblasts showed that miR-10b suppressed proliferation, migration, and pro-fibrotic gene expression, while promoting apoptosis under inflammatory conditions. Integrated target prediction and transcriptomic analyses identified Lpar2 as a direct miR-10b target, validated by luciferase reporter assay and confirmed at both mRNA and protein levels. miR-10b overexpression attenuated lysophosphatidic acid (LPA)-induced fibroblast proliferation and collagen I/III synthesis, supporting an anti-fibrotic role. In vivo inhibition of miR-10b in aged mice exacerbated post-infarction ventricular dilatation and wall thinning, accompanied by increased fibrotic remodeling markers, consistent with enhanced extracellular matrix remodeling, providing in vivo evidence for this regulatory axis. Collectively, these findings establish miR-10b as a protective regulator of post-infarction remodeling and in aging heart through suppression of Lpar2-mediated fibroblast activation highlighting its potential as a therapeutic target in age-associated cardiac fibrosis.

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Nastase-Rusu, E.-G., Marinescu-Colan, C.-I., Neculachi, C. A., Lupan, A.-M., Cosman, B. P., Publik, M. A., Liehn, E., Martelli, F., Preda, M. B., Burlacu, A.. 2026-07-06. miR-10b Mitigates Cardiac Fibrosis Associated with Aging and Myocardial Infarction via Attenuation of Lpar2 Signaling in Cardiac Fibroblasts. https://doi.org/10.64898/2026.07.02.736228

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