title: 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 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bang
authors.forename: Sandor
authors.initials: S
authors.lastname: Batkai
authors.forename: Seema
authors.initials: S
authors.lastname: Dangwal
authors.forename: Shashi Kumar
authors.initials: SK
authors.lastname: Gupta
authors.forename: Ariana
authors.initials: A
authors.lastname: Foinquinos
authors.forename: Angelika
authors.initials: A
authors.lastname: Holzmann
authors.forename: Annette
authors.initials: A
authors.lastname: Just
authors.forename: Janet
authors.initials: J
authors.lastname: Remke
authors.forename: Karina
authors.initials: K
authors.lastname: Zimmer
authors.forename: Andre
authors.initials: A
authors.lastname: Zeug
authors.forename: Evgeni
authors.initials: E
authors.lastname: Ponimaskin
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmiedl
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Rashi
authors.initials: R
authors.lastname: Halder
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wei
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
authors.forename: Jan
authors.initials: J
authors.lastname: Fiedler
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D055354:Exosomes / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008840:Microfilament Proteins / Q000096:biosynthesis; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510085:ENH protein, mouse; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D008840:Microfilament Proteins; C490754:Sorbs2 protein, rat; C546082:mirn21 microRNA, rat
references.citation: Physiol Rev. 1999 Jan;79(1):215-62
references.pmid: 9922372
references.citation: Mol Cell. 2009 Nov 13;36(3):431-44
references.pmid: 19917251
references.citation: RNA. 2010 Jan;16(1):43-56
references.pmid: 19917635
references.citation: J Biol Chem. 2010 Jun 4;285(23):17442-52
references.pmid: 20353945
references.citation: Curr Protoc Cell Biol. 2006 Apr;Chapter 3:Unit 3.22
references.pmid: 18228490
references.citation: Circ Res. 2010 Aug 6;107(3):348-56
references.pmid: 20538684
references.citation: N Engl J Med. 2008 Mar 27;358(13):1370-80
references.pmid: 18367740
references.citation: Curr Drug Targets. 2013 Sep;14(10):1185-91
references.pmid: 23834144
references.citation: Circulation. 2013 May 28;127(21):2097-106
references.pmid: 23625957
references.citation: J Clin Invest. 2013 May;123(5):2143-54
references.pmid: 23619365
references.citation: Nature. 2008 Dec 18;456(7224):980-4
references.pmid: 19043405
references.citation: Cell. 2001 Jul 27;106(2):145-55
references.pmid: 11511343
references.citation: J Cell Biochem. 2010 Oct 1;111(2):488-96
references.pmid: 20533300
references.citation: Circ Res. 2010 Jan 8;106(1):47-57
references.pmid: 20056945
references.citation: Cell. 2007 Apr 20;129(2):303-17
references.pmid: 17397913
references.citation: Immunobiology. 2013 Feb;218(2):255-62
references.pmid: 22698984
references.citation: Trends Cell Biol. 2009 Feb;19(2):43-51
references.pmid: 19144520
references.citation: PLoS One. 2012;7(4):e34688
references.pmid: 22529925
references.citation: J Biochem. 2006 Jul;140(1):13-21
references.pmid: 16877764
references.citation: J Immunol. 2007 Aug 1;179(3):1489-96
references.pmid: 17641014
references.citation: Blood. 2004 Nov 15;104(10):3257-66
references.pmid: 15284116
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5003-8
references.pmid: 21383194
references.citation: J Immunol. 2000 Aug 1;165(3):1259-65
references.pmid: 10903724
references.citation: Int Rev Cell Mol Biol. 2010;284:113-79
references.pmid: 20875630
references.citation: Circ J. 2008;72 Suppl A:A13-6
references.pmid: 18772527
references.citation: Nucleic Acids Res. 2013 Nov;41(21):9688-704
references.pmid: 23990326
references.citation: Int J Cancer. 2005 Feb 20;113(5):752-60
references.pmid: 15499615
references.citation: Nat Cell Biol. 2012 Feb 12;14(3):249-56
references.pmid: 22327366
references.citation: Circulation. 2009 Mar 10;119(9):1263-71
references.pmid: 19237659
references.citation: Circulation. 2007 Jul 17;116(3):258-67
references.pmid: 17606841
references.citation: Am J Physiol Cell Physiol. 2007 May;292(5):C1799-808
references.pmid: 17229813
references.citation: Genome Biol. 2010;11(10):R106
references.pmid: 20979621
references.citation: J Cell Physiol. 2005 Mar;202(3):891-9
references.pmid: 15389635
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6328-33
references.pmid: 20304794
references.citation: Nat Commun. 2012;3:1078
references.pmid: 23011132
references.citation: J Am Heart Assoc. 2013 Dec 16;2(6):e000565
references.pmid: 24342996
references.citation: Circ Res. 2010 Apr 2;106(6):1035-9
references.pmid: 20185794
references.citation: J Clin Invest. 2010 Jan;120(1):254-65
references.pmid: 20038803
references.citation: Nucleic Acids Res. 2010 Nov;38(20):7248-59
references.pmid: 20615901
references.citation: Circulation. 2014 Mar 4;129(9):1009-21
references.pmid: 24429688
references.citation: J Exp Med. 1996 Mar 1;183(3):1161-72
references.pmid: 8642258
references.citation: N Engl J Med. 2013 May 2;368(18):1685-94
references.pmid: 23534542
references.citation: Gastroenterology. 2013 Oct;145(4):853-64.e9
references.pmid: 23770133
references.citation: Methods Enzymol. 2008;449:373-93
references.pmid: 19215768
references.citation: PLoS One. 2008;3(11):e3694
references.pmid: 19002258
references.citation: J Cell Sci. 2013 Mar 15;126(Pt 6):1517-30
references.pmid: 23418359
references.citation: Oncol Rep. 2012 Nov;28(5):1551-8
references.pmid: 22895844
references.citation: Cell Struct Funct. 2002 Feb;27(1):1-7
references.pmid: 11937713
references.citation: Mol Cell. 2009 Nov 13;36(3):445-56
references.pmid: 19917252
references.citation: Nat Commun. 2011;2:282
references.pmid: 21505438
references.citation: BMC Genomics. 2010 May 07;11:288
references.pmid: 20459673