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Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy

Open access
Bang, Claudia, Batkai, Sandor, Dangwal, Seema, Gupta, Shashi Kumar, Foinquinos, Ariana, Holzmann, Angelika, Just, Annette, Remke, Janet, Zimmer, Karina, Zeug, Andre, Ponimaskin, Evgeni, Schmiedl, Andreas, Yin, Xiaoke, Mayr, Manuel, Halder, Rashi, Fischer, Andre, Engelhardt, Stefan, Wei, Yuanyuan, Schober, Andreas, Fiedler, Jan, Thum, Thomas·2014·Journal of Clinical Investigation

Abstract

In response to stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and pathological growth of cardiomyocytes (hypertrophy), which contribute to heart failure. Alterations in microRNA (miRNA) levels are associated with dysfunctional gene expression profiles associated with many cardiovascular disease conditions; however, miRNAs have emerged recently as paracrine signaling mediators. Thus, we investigated a potential paracrine miRNA crosstalk between cardiac fibroblasts and cardiomyocytes and found that cardiac fibroblasts secrete miRNA-enriched exosomes. Surprisingly, evaluation of the miRNA content of cardiac fibroblast-derived exosomes revealed a relatively high abundance of many miRNA passenger strands ("star" miRNAs), which normally undergo intracellular degradation. Using confocal imaging and coculture assays, we identified fibroblast exosomal-derived miR-21_3p (miR-21*) as a potent paracrine-acting RNA molecule that induces cardiomyocyte hypertrophy. Proteome profiling identified sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) as miR-21* targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of miR-21* in a mouse model of Ang II-induced cardiac hypertrophy attenuated pathology. These findings demonstrate that cardiac fibroblasts secrete star miRNA-enriched exosomes and identify fibroblast-derived miR-21* as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target.

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Metadata

Authors
Bang, C., Batkai, S., Dangwal, S., Gupta, S. K., Foinquinos, A., Holzmann, A., Just, A., Remke, J., Zimmer, K., Zeug, A., Ponimaskin, E., Schmiedl, A., Yin, X., Mayr, M., Halder, R., Fischer, A., Engelhardt, S., Wei, Y., Schober, A., Fiedler, J., & Thum, T.
Venue
Journal of Clinical Investigation
Published
2014-04-17
Volume
124
Issue
5
Pages
2136-2146
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2109934828
Cited by
979
References
8
FWCI
32.85
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. https://app.cochat.ai/papers/10.1172/jci70577
The paper
Bang, C., Batkai, S., Dangwal, S., Gupta, S. K., Foinquinos, A., Holzmann, A., Just, A., Remke, J., Zimmer, K., Zeug, A., Ponimaskin, E., Schmiedl, A., Yin, X., Mayr, M., Halder, R., Fischer, A., Engelhardt, S., Wei, Y., Schober, A., . . . Thum, T. (2014). Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. Journal of Clinical Investigation. https://doi.org/10.1172/jci70577

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.