567 Study Hypothesis During the past few years, increasing studies have identified microRNAs to be present in the circulation, either encapsulated in microvesicles or exosomes or associated with RNA-binding proteins or lipoproteins. 1 Recent studies have suggested that cir- culating microRNAs may function in cell–cell communication, being transported from one cell type to another and regulating target gene expression in recipient cells. 2,3 Although it has been generally thought that the passenger strand of the microRNA duplex is degraded during microRNA biogenesis and only the guide strand of the microRNA duplex is selected to become the mature functional microRNA, there is mounting evidence that passenger strand microRNAs can also target mRNAs and have biological functions in pathologies such as cancer. 4,5 In the current study, Bang et al 6 present evidence that exosomes pro- duced by cardiac fibroblasts contain passenger strand microR- NAs, which are transferred to cardiomyocytes and play a role in the development of fibroblast-derived cardiomyocyte hyper- trophy, revealing a novel method of paracrine communication between cardiac fibroblasts and cardiomyocytes. How Was the Hypothesis Tested? The authors 6 used electron microscopy to demonstrate the abil- ity of neonatal rat cardiac fibroblasts to produce and secrete exosomes (fibroblast-derived exosomes). They further con- firmed the identity of the exosomes by performing Western blotting and fluorescence-activated cell sorting analyses for the presence of an exosomal marker protein. To assess the microRNA content of fibroblast-derived exosomes, the authors used a microRNA profiling assay and, in particular, detected the presence of the passenger strand of microRNA-21 (miR- 21*). Expression of miR-21* in fibroblast-derived exosomes was confirmed by quantitative real time-polymerase chain reaction and RNA sequencing. Using confocal microscopy and coculture assays, the authors investigated the ability of fibroblast-derived exosomes and microRNAs to be transported to and taken up into cardiomyocytes. Moreover, they tested whether exosome-derived miR-21* modulated cardiomyocyte cell size by incubating cardiomyocytes with exosomes isolated from the conditioned medium of fibroblasts that were trans- fected with a precursor of miR-21* (pre–miR-21*). To further study the role of miR-21* in cardiomyocytes, the authors per- formed proteome profiling in cardiomyocytes transfected with pre–miR-21* or a control microRNA to identify potential tar- gets that are regulated by miR-21*. Proteome profiling analy- sis revealed that sorbin and SH3 domain-containing protein 2 (SORBS2) was strongly downregulated and PDZ and LIM domain 5 (PDLIM5), which had been previously implicated in cardiomyopathy, 7 was also among the downregulated tar- gets. The authors examined whether SORBS2 and PDLIM5 play a role in cardiomyocyte hypertrophy by using small interfering RNAs to knockdown either SORBS2 or PDLIM5 (Circ Cardiovasc Genet. 2014;7:567-568.) © 2014 American Heart Association, Inc. Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org DOI: 10.1161/CIRCGENETICS.114.000805 From the Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA (C.W.); and the Early Career Committee of the American Heart Association Functional Genomics and Translational Biology Council, Dallas, TX (P.A.). Correspondence to Pankaj Arora, MD, Division of Cardiology, University of Alabama at Birmingham, 1808 7th Ave S, BDB 201, Birmingham, AL 35294. E-mail parora@uabmc.edu MicroRNA Passenger Strand Orchestral Symphony of Paracrine Signaling Connie Wu, PhD; Pankaj Arora, MD Cardiovascular Genetics: A News Round-Up 1. Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res. 2012;110:483–495. 2. Hergenreider E, Heydt S, Tréguer K, Boettger T, Horrevoets AJ, Zei- her AM, et al. Atheroprotective communication between endothe- lial cells and smooth muscle cells through miRNAs. Nat Cell Biol. 2012;14:249–256. 3. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13:423–433. 4. Yang X, Du WW, Li H, Liu F, Khorshidi A, Rutnam ZJ, et al. Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion. Nucleic Acids Res. 2013;41:9688–9704. 5. Shan SW, Fang L, Shatseva T, Rutnam ZJ, Yang X, Du W, et al. Mature miR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7 and vimentin in different signal pathways. J Cell Sci. 2013;126(pt 6):1517–1530. 6. Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A, et al. Cardiac fibroblast-derived microRNA passenger strand-en- riched exosomes mediate cardiomyocyte hypertrophy. 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