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

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 paracrineacting 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.

Myocardial connexin-43 and PKC signalling are involved in adaptation of the heart to irradiation-induced injury: Implication of miR-1 and miR-21

“…These activation of cardiac remodelling in response to irradiation which may accelerate over time since miR-21 activates fibroblasts (Thum et al 2008;Bauersachs 2012;van Rooij et al 2012) and enhanced proteolytic activity of MMP-2 promotes fibroblast migration (Bauersachs 2012). Moreover, it has been recently identified that fibroblast exosomalderived miR-21 is like a potent paracrine acting RNA molecule that induces cardiomyocyte hypertrophy (Bang et al 2014). In response to stress, the heart undergoes an extensive cardiac remodelling resulting in cardiac hypertrophy and fibrosis that over time contribute to heart failure.…”

Exosomes as a novel pathway for regulating development and diseases of the skin (Review)

“…Barrier function is an irreplaceable function of the skin (16), and the skin contains various accessory organs (17). There are multiple types of cells that secrete exosomes in the skin, for example keratinocytes, fibroblasts and adipocytes secrete exosomes into other cells or body fluids to participate in biological activity (6,18,19).…”

MicroRNA and Its Role in Cardiovascular Disease

“…Recent works reported by Bang et al [41] showed that in response to stress oncadio fibroblast secrete miRNA enriched exosomes, miR-21 also called "star" …”