This Article Full Text Full Text (PDF) Data Supplement Correction Correction (v116,pe135) All Versions of this Article: 116/3/258    most recent CIRCULATIONAHA.107.687947v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thum, T. Articles by Bauersachs, J. Search for Related Content PubMed PubMed Citation Articles by Thum, T. Articles by Bauersachs, J. Pubmed/NCBI databases Gene GEO Profiles Medline Plus Health Information Heart Failure Related Collections Congestive Physiological and pathological control of gene expression

(Circulation. 2007;116:258-267.)
© 2007 American Heart Association, Inc.

Heart Failure

MicroRNAs in the Human Heart

A Clue to Fetal Gene Reprogramming in Heart Failure

Thomas Thum, MD; Paolo Galuppo, PhD; Christian Wolf; Jan Fiedler, BS; Susanne Kneitz, PhD; Linda W. van Laake, MD; Pieter A. Doevendans, MD, PhD; Christine L. Mummery, PhD; Jürgen Borlak, PhD; Axel Haverich, MD; Carina Gross, BS; Stefan Engelhardt, MD, PhD; Georg Ertl, MD; Johann Bauersachs, MD

From the University of Würzburg, University Hospital, Department of Internal Medicine I, Cardiology, Würzburg, Germany (T.T., P.G., C.W., J.F, G.E., J.B.); University of Würzburg, Interdisciplinary Center for Clinical Research, Junior Research Group Cardiac Wounding and Healing, Würzburg, Germany (T.T., J.F.); University of Würzburg, Interdisciplinary Center for Clinical Research, Microarray Core Facility, Würzburg, Germany (S.K.); Hubrecht Laboratory and the Heart Lung Institute, University of Utrecht Medical Center, Utrecht, the Netherlands (L.W.v.L., P.A.D., C.L.M.); Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (J.B.); Medical School Hannover, Department of Cardiac and Thoracic Surgery, Hannover, Germany (A.H.); and University of Würzburg, Rudolf-Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany (C.G., S.E.).

Correspondence to Thomas Thum, MD, Universitätsklinikum, Medizinische Klinik I, Kardiologie, Josef Schneider Strasse 2, 97080 Würzburg, Germany (e-mail Thum_T{at}klinik.uni-wuerzburg.de); or Johann Bauersachs, MD, Universitätsklinikum, Medizinische Klinik I, Kardiologie, Josef Schneider Strasse 2, 97080 Würzburg, Germany (e-mail Bauersachs_J@medizin.uni-wuerzburg.de).

Received January 2, 2007; accepted May 11, 2007.

Background— Chronic heart failure is characterized by left ventricular remodeling and reactivation of a fetal gene program; the underlying mechanisms are only partly understood. Here we provide evidence that cardiac microRNAs, recently discovered key regulators of gene expression, contribute to the transcriptional changes observed in heart failure.

Methods and Results— Cardiac transcriptome analyses revealed striking similarities between fetal and failing human heart tissue. Using microRNA arrays, we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. Bioinformatic analysis demonstrated a striking concordance between regulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3' untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy as well as changes in gene expression comparable to the failing heart.

Conclusions— Our data support a novel mode of regulation for the transcriptional changes in cardiac failure. Reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				F. Fazi and C. Nervi MicroRNA: basic mechanisms and transcriptional regulatory networks for cell fate determination Cardiovasc Res, June 30, 2008; (2008) cvn151v2. [Abstract] [Full Text] [PDF]

				T. Thum, D. Catalucci, and J. Bauersachs MicroRNAs: novel regulators in cardiac development and disease Cardiovasc Res, June 23, 2008; (2008) cvn137v2. [Abstract] [Full Text] [PDF]

				J.-F. Chen, E. P. Murchison, R. Tang, T. E. Callis, M. Tatsuguchi, Z. Deng, M. Rojas, S. M. Hammond, M. D. Schneider, C. H. Selzman, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure PNAS, February 12, 2008; 105(6): 2111 - 2116. [Abstract] [Full Text] [PDF]

				T. E. Callis, Z. Deng, J.-F. Chen, and D.-Z. Wang Muscling Through the microRNA World Experimental Biology and Medicine, February 1, 2008; 233(2): 131 - 138. [Abstract] [Full Text] [PDF]

				T. P. Cappola Molecular Remodeling in Human Heart Failure J. Am. Coll. Cardiol., January 15, 2008; 51(2): 137 - 138. [Full Text] [PDF]

				M. V.G. Latronico, D. Catalucci, and G. Condorelli Emerging Role of MicroRNAs in Cardiovascular Biology Circ. Res., December 7, 2007; 101(12): 1225 - 1236. [Abstract] [Full Text] [PDF]

				S. Ikeda, S. W. Kong, J. Lu, E. Bisping, H. Zhang, P. D. Allen, T. R. Golub, B. Pieske, and W. T. Pu Altered microRNA expression in human heart disease Physiol Genomics, November 14, 2007; 31(3): 367 - 373. [Abstract] [Full Text] [PDF]

				E. van Rooij and E. N. Olson microRNAs put their signatures on the heart Physiol Genomics, November 14, 2007; 31(3): 365 - 366. [Full Text] [PDF]