Comparative RNA-sequencing Analysis of Myocardial and Circulating Small RNAs in Human Heart Failure and Their Utility As Biomarkers

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2014 Jul 12

PMID 25012294

Citations 130

Authors

Kemal Marc Akat

DVesharronne Moore-McGriff

Pavel Morozov

Miguel Brown

Tasos Gogakos

Joel Correa Da Rosa

Aleksandra Mihailovic

Markus Sauer

Ruiping Ji

Aarthi Ramarathnam

Hana Totary-Jain

Zev Williams

Thomas Tuschl

P Christian Schulze

Affiliations

Soon will be listed here.

Abstract

Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNA-target-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers.

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References

Dhahbi J, Spindler S, Atamna H, Yamakawa A, Boffelli D, Mote P . 5' tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. BMC Genomics. 2013; 14:298. PMC: 3654920. DOI: 10.1186/1471-2164-14-298. View

Zhao Y, Ransom J, Li A, Vedantham V, von Drehle M, Muth A . Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129(2):303-17. DOI: 10.1016/j.cell.2007.03.030. View

Kapranov P, Ozsolak F, Milos P . Profiling of short RNAs using Helicos single-molecule sequencing. Methods Mol Biol. 2011; 822:219-32. PMC: 3272357. DOI: 10.1007/978-1-61779-427-8_15. View

Porrello E, Johnson B, Aurora A, Simpson E, Nam Y, Matkovich S . MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes. Circ Res. 2011; 109(6):670-9. PMC: 3167208. DOI: 10.1161/CIRCRESAHA.111.248880. View

Brown M, Suryawanshi H, Hafner M, Farazi T, Tuschl T . Mammalian miRNA curation through next-generation sequencing. Front Genet. 2013; 4:145. PMC: 3731538. DOI: 10.3389/fgene.2013.00145. View

Yang K, Yamada K, Patel A, Topkara V, George I, Cheema F . Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation. 2014; 129(9):1009-21. PMC: 3967509. DOI: 10.1161/CIRCULATIONAHA.113.003863. View

Naga Prasad S, Duan Z, Gupta M, Surampudi V, Volinia S, Calin G . Unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks. J Biol Chem. 2009; 284(40):27487-99. PMC: 2785678. DOI: 10.1074/jbc.M109.036541. View

Van Rooij E, Quiat D, Johnson B, Sutherland L, Qi X, Richardson J . A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell. 2009; 17(5):662-73. PMC: 2796371. DOI: 10.1016/j.devcel.2009.10.013. View

Ji X, Takahashi R, Hiura Y, Hirokawa G, Fukushima Y, Iwai N . Plasma miR-208 as a biomarker of myocardial injury. Clin Chem. 2009; 55(11):1944-9. DOI: 10.1373/clinchem.2009.125310. View

10.

Braun J, Huntzinger E, Izaurralde E . The role of GW182 proteins in miRNA-mediated gene silencing. Adv Exp Med Biol. 2012; 768:147-63. DOI: 10.1007/978-1-4614-5107-5_9. View

11.

Van Rooij E, Olson E . MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov. 2012; 11(11):860-72. PMC: 6813819. DOI: 10.1038/nrd3864. View

12.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View

13.

Sucharov C, Bristow M, Port J . miRNA expression in the failing human heart: functional correlates. J Mol Cell Cardiol. 2008; 45(2):185-92. PMC: 2561965. DOI: 10.1016/j.yjmcc.2008.04.014. View

14.

Hafner M, Renwick N, Farazi T, Mihailovic A, Pena J, Tuschl T . Barcoded cDNA library preparation for small RNA profiling by next-generation sequencing. Methods. 2012; 58(2):164-70. PMC: 3508525. DOI: 10.1016/j.ymeth.2012.07.030. View

15.

Guo H, Ingolia N, Weissman J, Bartel D . Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010; 466(7308):835-40. PMC: 2990499. DOI: 10.1038/nature09267. View

16.

Krutzfeldt J, Rajewsky N, Braich R, Rajeev K, Tuschl T, Manoharan M . Silencing of microRNAs in vivo with 'antagomirs'. Nature. 2005; 438(7068):685-9. DOI: 10.1038/nature04303. View

17.

Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B . The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 2007; 13(4):486-91. DOI: 10.1038/nm1569. View

18.

Ikeda S, Kong S, Lu J, Bisping E, Zhang H, Allen P . Altered microRNA expression in human heart disease. Physiol Genomics. 2007; 31(3):367-73. DOI: 10.1152/physiolgenomics.00144.2007. View

19.

Fang Z, Rajewsky N . The impact of miRNA target sites in coding sequences and in 3'UTRs. PLoS One. 2011; 6(3):e18067. PMC: 3062573. DOI: 10.1371/journal.pone.0018067. View

20.

Weiland M, Gao X, Zhou L, Mi Q . Small RNAs have a large impact: circulating microRNAs as biomarkers for human diseases. RNA Biol. 2012; 9(6):850-9. DOI: 10.4161/rna.20378. View