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

Author

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, and Thum, Thomas

Subjects
MicroRNA -- Properties, Fibroblasts -- Genetic aspects, Heart enlargement -- Diagnosis, Health care industry
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.sup.*]) 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.sup.*] targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of [miR-21.sup.*] 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.sup.*] as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target., Introduction Cardiac remodeling is a hallmark in the progression of many cardiovascular diseases and is characterized by cardiomyocyte hypertrophy and cardiac fibrosis that lead often to heart failure, a major [...]

Published
2014
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6. Functional MicroRNA Library Screening Identifies the HypoxaMiR MiR-24 as a Potent Regulator of Smooth Muscle Cell Proliferation and Vascularization

Author

Fiedler, Jan, primary, Stöhr, Andrea, additional, Gupta, Shashi Kumar, additional, Hartmann, Dorothee, additional, Holzmann, Angelika, additional, Just, Annette, additional, Hansen, Arne, additional, Hilfiker-Kleiner, Denise, additional, Eschenhagen, Thomas, additional, and Thum, Thomas, additional

Published
2014
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10. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy

Author

Ucar, Ahmet, primary, Gupta, Shashi K., additional, Fiedler, Jan, additional, Erikci, Erdem, additional, Kardasinski, Michal, additional, Batkai, Sandor, additional, Dangwal, Seema, additional, Kumarswamy, Regalla, additional, Bang, Claudia, additional, Holzmann, Angelika, additional, Remke, Janet, additional, Caprio, Massimiliano, additional, Jentzsch, Claudia, additional, Engelhardt, Stefan, additional, Geisendorf, Sabine, additional, Glas, Carolina, additional, Hofmann, Thomas G., additional, Nessling, Michelle, additional, Richter, Karsten, additional, Schiffer, Mario, additional, Carrier, Lucie, additional, Napp, L. Christian, additional, Bauersachs, Johann, additional, Chowdhury, Kamal, additional, and Thum, Thomas, additional

Published
2012
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