A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure.
Journal: 2007/January - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
Diverse forms of injury and stress evoke a hypertrophic growth response in adult cardiac myocytes, which is characterized by an increase in cell size, enhanced protein synthesis, assembly of sarcomeres, and reactivation of fetal genes, often culminating in heart failure and sudden death. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs that were regulated during cardiac hypertrophy and heart failure. We describe >12 miRNAs that are up- or down-regulated in cardiac tissue from mice in response to transverse aortic constriction or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs was sufficient to induce hypertrophy in cultured cardiomyocytes. Similarly, cardiac overexpression of miR-195, which was up-regulated during cardiac hypertrophy, resulted in pathological cardiac growth and heart failure in transgenic mice. These findings reveal an important role for specific miRNAs in the control of hypertrophic growth and chamber remodeling of the heart in response to pathological signaling and point to miRNAs as potential therapeutic targets in heart disease.
Relations:
Content
Citations
(526)
References
(33)
Diseases
(1)
Conditions
(1)
Chemicals
(1)
Genes
(3)
Organisms
(3)
Processes
(2)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Proc Natl Acad Sci U S A 103(48): 18255-18260

A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure

Departments of *Molecular Biology,
Internal Medicine, and
Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148
To whom correspondence should be addressed. E-mail: ude.nretsewhtuostu@noslo.cire

Contributed by Eric N. Olson, October 4, 2006

.

Author contributions: E.v.R., L.B.S., and A.H.W. performed research; N.L., J.M., R.D.G., and J.A.R. contributed new reagents/analytic tools; E.N.O. analyzed data; and E.v.R. and E.N.O. wrote the paper.

Received 2006 Oct 1

Abstract

Diverse forms of injury and stress evoke a hypertrophic growth response in adult cardiac myocytes, which is characterized by an increase in cell size, enhanced protein synthesis, assembly of sarcomeres, and reactivation of fetal genes, often culminating in heart failure and sudden death. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs that were regulated during cardiac hypertrophy and heart failure. We describe >12 miRNAs that are up- or down-regulated in cardiac tissue from mice in response to transverse aortic constriction or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs was sufficient to induce hypertrophy in cultured cardiomyocytes. Similarly, cardiac overexpression of miR-195, which was up-regulated during cardiac hypertrophy, resulted in pathological cardiac growth and heart failure in transgenic mice. These findings reveal an important role for specific miRNAs in the control of hypertrophic growth and chamber remodeling of the heart in response to pathological signaling and point to miRNAs as potential therapeutic targets in heart disease.

Keywords: calcineurin, myosin heavy chain, thoracic aortic banding, cardiomyocytes
Abstract

The adult heart is a dynamic organ capable of significant remodeling and hypertrophic growth as a means of adapting function to altered workloads or injury. Hemodynamic stress or neuroendocrine signaling associated with myocardial infarction, hypertension, aortic stenosis, and valvular dysfunction evoke a pathologic remodeling response through the activation of intracellular signaling pathways and transcriptional mediators in cardiac myocytes (reviewed in ref. 1). Activation of these molecular pathways enhances cardiomyocyte size and protein synthesis, induces the assembly of sarcomeres, and causes re-expression of fetal cardiac genes (2, 3). Although aspects of the hypertrophic response after acute and chronic stress may initially augment cardiac output, prolonged hypertrophy is a major predictor of heart failure and sudden death. There have been major advances in the identification of genes and signaling pathways involved in this disease process, but the overall complexity of hypertrophic remodeling suggests that additional regulatory mechanisms remain to be identified (4).

MicroRNAs (miRNAs) are small, noncoding RNAs of 18–25 nt that regulate gene expression in a sequence-specific manner. miRNAs are transcribed by RNA polymerase II as primary transcripts that are usually several thousand bases in length and are subsequently processed into smaller, functional RNA fragments. Primary transcripts are first processed into a 70- to 100-nt hairpin-shaped precursor within the nucleus by the action of the RNase Drosha, after which they are transported to the cytoplasm and cleaved by Dicer, releasing the mature double-stranded miRNA (reviewed in ref. 5). A single strand of the mature miRNA is incorporated into the RNA-induced silencing complex to enable its interaction with target mRNA sequences. Binding of mature miRNAs to mRNAs negatively influences the expression of specific proteins by either degradation of the bound mRNA target or direct translational inhibition. The high sequence conservation of many miRNAs across metazoan species suggests strong evolutionary pressure and participation in essential biologic processes (6, 7). Indeed, miRNAs have been shown to play fundamental roles in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis in species ranging from Caenorhabditis elegans and Drosophila melanogaster to humans (811).

In light of their involvement in modulating cellular phenotypes, we hypothesized that miRNAs might play a role in regulating the response of the heart to cardiac stress, which is known to result in transcriptional and translational changes in gene expression. Here, we describe >12 miRNAs that are modulated in hypertrophic or failing hearts from mice and humans. Overexpression of selected miRNAs in cardiomyocytes in vitro induced cardiac hypertrophy and overexpression of miR-195, a stress inducible miRNA, in transgenic (Tg) mice resulted in pathological cardiac remodeling and heart failure. These findings point to miRNAs as key regulators of cardiac growth and function and potential therapeutic targets in the setting of heart disease.

Click here to view.

Acknowledgments

We thank Dr. Joseph Hill (University of Texas Southwestern Medical Center) for providing cardiac tissue from animals that received TAB; Erik Bush (Myogen, Inc.) for the human cardiac samples; Drs. Rhonda Bassel-Duby and Dan Garry for comments on the manuscript; and Cheryl Nolen for excellent technical assistance. This work was supported by grants from the National Institutes of Health, the Donald W. Reynolds Cardiovascular Clinical Research Center, and the Robert A. Welch Foundation (to E.N.O.).

Acknowledgments

Abbreviations

miRNAmicroRNA
TABthoracic aortic banding
CnAcalcineurin A
Tgtransgenic
MHCmyosin heavy chain
MOImultiplicity of infection.
Abbreviations

Footnotes

The authors declare no conflict of interest.

Footnotes

References

  • 1. Arad M, Seidman JG, Seidman CE. Hum Mol Genet. 2002;11:2499–2506.[PubMed]
  • 2. Dorn GW, 2nd, Robbins J, Sugden PH. Circ Res. 2003;92:1171–1175.[PubMed]
  • 3. Chien KR. Cell. 1999;98:555–558.[PubMed]
  • 4. Frey N, Olson EN. Annu Rev Physiol. 2003;65:45–79.[PubMed]
  • 5. Bartel DP. Cell. 2004;116:281–297.[PubMed]
  • 6. Moss EG, Tang L. Dev Biol. 2003;258:432–442.[PubMed]
  • 7. Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P, et al Nature. 2000;408:86–89.[PubMed][Google Scholar]
  • 8. Esquela-Kerscher A, Slack FJ. Nat Rev Cancer. 2006;6:259–269.[PubMed]
  • 9. Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N, Croce CM. Proc Natl Acad Sci USA. 2006;103:7024–7029.
  • 10. Hammond SM. Curr Opin Genet Dev. 2006;16:4–9.[PubMed]
  • 11. Ambros V. Cell. 2003;113:673–676.[PubMed]
  • 12. Hill JA, Karimi M, Kutschke W, Davisson RL, Zimmerman K, Wang Z, Kerber RE, Weiss RM. Circulation. 2000;101:2863–2869.[PubMed]
  • 13. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. Cell. 1998;93:215–228.
  • 14. Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A, Bentwich I, Einav U, Gilad S, Hurban P, Karov Y, et al Genome Res. 2004;14:2486–2494.[Google Scholar]
  • 15. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Genome Biol. 2004;5:R13.
  • 16. Shingara J, Keiger K, Shelton J, Laosinchai-Wolf W, Powers P, Conrad R, Brown D, Labourier E. RNA. 2005;11:1461–1470.
  • 17. Babak T, Zhang W, Morris Q, Blencowe BJ, Hughes TR. RNA. 2004;10:1813–1819.
  • 18. Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M, Dumitru CD, Shimizu M, Zupo S, Dono M, et al Proc Natl Acad Sci USA. 2004;101:9740–9744.[Google Scholar]
  • 19. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN. EMBO J. 2004;23:4051–4060.
  • 20. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Cell. 2002;110:479–488.
  • 21. Obernosterer G, Leuschner PJ, Alenius M, Martinez J. RNA. 2006;12:1161–1167.
  • 22. Chan JA, Krichevsky AM, Kosik KS. Cancer Res. 2005;65:6029–6033.[PubMed]
  • 23. Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, Calin GA, Volinia S, Liu CG, Scarpa A, Croce CM. J Clin Oncol. 2006;24:4677–4684.[PubMed]
  • 24. Kawasaki H, Taira K. Nucleic Acids Symp Ser. 2003;3:243–244.[PubMed]
  • 25. Lee YS, Kim HK, Chung S, Kim KS, Dutta A. J Biol Chem. 2005;280:16635–16641.[PubMed]
  • 26. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, et al Cancer Res. 2005;65:7065–7070.[PubMed][Google Scholar]
  • 27. Zhao Y, Samal E, Srivastava D. Nature. 2005;436:214–220.[PubMed]
  • 28. Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang DZ. Nat Genet. 2006;38:228–233.
  • 29. Parlakian A, Charvet C, Escoubet B, Mericskay M, Molkentin JD, Gary-Bobo G, De Windt LJ, Ludosky MA, Paulin D, Daegelen D, et al Circulation. 2005;112:2930–2939.[PubMed][Google Scholar]
  • 30. Goff LA, Yang M, Bowers J, Getts RC, Padgett RW, Hart RP. RNA. 2005;2:e9–e16.[PubMed]
  • 31. Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. J Clin Invest. 2006;116:1853–1864.
  • 32. Gulick J, Subramaniam A, Neumann J, Robbins J. J Biol Chem. 1991;266:9180–9185.[PubMed]
  • 33. Shelton JM, Lee MH, Richardson JA, Patel SB. J Lipid Res. 2000;41:532–537.[PubMed]
  • 34. Harrison BC, Kim MS, van Rooij E, Plato CF, Papst PJ, Vega RB, McAnally JA, Richardson JA, Bassel-Duby R, Olson EN, McKinsey TA. Mol Cell Biol. 2006;26:3875–3888.
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.