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The transcriptional repressor Nab1 is a specific regulator of pathological cardiac hypertrophy

Nature Medicine volume 11, pages 837–844 (2005)Cite this article

Abstract

Hypertrophy represents the major physiological response of the heart to adapt to chronically enhanced workload, but is also crucial in the development of heart failure. Although we know of numerous inducers of cardiac hypertrophy, little is known about mechanisms that limit cardiac hypertrophy. Here, we describe the transcriptional repressor NAB1 as an endogenous regulator of cardiac growth. We identified NAB1 as being upregulated in both mouse and human heart failure. Nab1 is highly expressed in mammalian cardiac myocytes and it inhibited cardiomyocyte hypertrophy through repression of its targets, transcription factor Egr. Transgenic mice with cardiac-specific overexpression of Nab1 showed that Nab1 is a potent inhibitor of cardiac growth in response to pathological stimuli in vivo. Nab1 overexpression suppressed adrenergically induced and pressure overload–induced hypertrophy, whereas physiological growth during development and in response to exercise was not affected. These findings implicate the Nab1-Egr1 axis as a crucial regulator of pathological cardiac growth.

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Figure 1: Upregulation of Nab1 in cardiac hypertrophy and heart failure.
Figure 2: Generation of Nab1 transgenic mice.
Figure 3: Nab1 regulates cardiomyocyte growth through interaction with Egr1.
Figure 4: Overexpression of Nab1 and deletion of Egr1 protect from pathological cardiac hypertrophy.
Figure 5: Nab1 regulates a specific subset of target genes in the heart.
Figure 6: Nab1 does not affect exercise-induced physiological hypertrophy.

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References

  1. Towbin, J.A. & Bowles, N.E. The failing heart. Nature 415, 227–233 (2002).

    Article  CAS  Google Scholar 

  2. Dorn, G.W., II, Robbins, J. & Sugden, P.H. Phenotyping hypertrophy: eschew obfuscation. Circ. Res. 92, 1171–1175 (2003).

    Article  CAS  Google Scholar 

  3. Lohse, M.J., Engelhardt, S. & Eschenhagen, T. What is the role of b-adrenergic signaling in heart failure? Circ. Res. 93, 896–906 (2003).

    Article  CAS  Google Scholar 

  4. Molkentin, J.D. & Dorn, I.G., II Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu. Rev. Physiol. 63, 391–426 (2001).

    Article  CAS  Google Scholar 

  5. Sussman, M.A. et al. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science 281, 1690–1693 (1998).

    Article  CAS  Google Scholar 

  6. Molkentin, J.D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

    Article  CAS  Google Scholar 

  7. Zhang, C.L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    Article  CAS  Google Scholar 

  8. Chien, K.R. & Olson, E.N. Converging pathways and principles in heart development and disease: CV@CSH. Cell 110, 153–162 (2002).

    Article  CAS  Google Scholar 

  9. Russo, M.W., Sevetson, B.R. & Milbrandt, J. Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription. Proc. Natl Acad. Sci. USA 92, 6873–6877 (1995).

    Article  CAS  Google Scholar 

  10. Swirnoff, A.H. et al. Nab1, a corepressor of NGFI-A (Egr-1), contains an active transcriptional repression domain. Mol. Cell. Biol. 18, 512–524 (1998).

    Article  CAS  Google Scholar 

  11. Thiel, G. & Cibelli, G. Regulation of life and death by the zinc finger transcription factor Egr-1. J. Cell. Physiol. 193, 287–292 (2002).

    Article  CAS  Google Scholar 

  12. Warner, L.E. et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat. Genet. 18, 382–384 (1998).

    Article  CAS  Google Scholar 

  13. Engelhardt, S., Hein, L., Wiesmann, F. & Lohse, M.J. Progressive hypertrophy and heart failure in β1-adrenergic receptor transgenic mice. Proc. Natl Acad. Sci. USA 96, 7059–7064 (1999).

    Article  CAS  Google Scholar 

  14. Topilko, P. et al. Krox-20 controls myelination in the peripheral nervous system. Nature 371, 796–799 (1994).

    Article  CAS  Google Scholar 

  15. Svaren, J. et al. Novel mutants of NAB corepressors enhance activation by Egr transactivators. EMBO J. 17, 6010–6019 (1998).

    Article  CAS  Google Scholar 

  16. Allen, D.L. et al. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J. Appl. Physiol. 90, 1900–1908 (2001).

    Article  CAS  Google Scholar 

  17. Frey, N., Katus, H.A., Olson, E.N. & Hill, J.A. Hypertrophy of the heart: a new therapeutic target? Circulation 109, 1580–1589 (2004).

    Article  Google Scholar 

  18. Esposito, G. et al. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 105, 85–92 (2002).

    Article  CAS  Google Scholar 

  19. Hill, J.A. et al. Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. J. Biol. Chem. 277, 10251–10255 (2002).

    Article  CAS  Google Scholar 

  20. Rapacciuolo, A. et al. Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy. J. Am. Coll. Cardiol. 38, 876–882 (2001).

    Article  CAS  Google Scholar 

  21. Levy, D., Garrison, R.J., Savage, D.D., Kannel, W.B. & Castelli, W.P. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med. 322, 1561–1566 (1990).

    Article  CAS  Google Scholar 

  22. Yasukawa, H. et al. The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury. J. Clin. Invest. 111, 469–478 (2003).

    Article  CAS  Google Scholar 

  23. Rothermel, B.A. et al. Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo . Proc. Natl Acad. Sci. USA 98, 3328–3333 (2001).

    Article  CAS  Google Scholar 

  24. Bueno, O.F. et al. The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo . Circ. Res. 88, 88–96 (2001).

    Article  CAS  Google Scholar 

  25. Crackower, M.A. et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737–749 (2002).

    Article  CAS  Google Scholar 

  26. Milbrandt, J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science 238, 797–799 (1987).

    Article  CAS  Google Scholar 

  27. Svaren, J. et al. NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli. Mol. Cell. Biol. 16, 3545–3553 (1996).

    Article  CAS  Google Scholar 

  28. Gashler, A. & Sukhatme, V.P. Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog. Nucleic Acid Res. Mol. Biol. 50, 191–224 (1995).

    Article  CAS  Google Scholar 

  29. Lee, S.L. et al. Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1). Science 273, 1219–1221 (1996).

    Article  CAS  Google Scholar 

  30. Neyses, L. et al. Induction of immediate-early genes by angiotensin II and endothelin-1 in adult rat cardiomyocytes. J. Hypertens. 11, 927–934 (1993).

    Article  CAS  Google Scholar 

  31. Neyses, L., Nouskas, J. & Vetter, H. Inhibition of endothelin-1 induced myocardial protein synthesis by an antisense oligonucleotide against the early growth response gene-1. Biochem. Biophys. Res. Commun. 181, 22–27 (1991).

    Article  CAS  Google Scholar 

  32. Sadoshima, J., Jahn, L., Takahashi, T., Kulik, T.J. & Izumo, S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J. Biol. Chem. 267, 10551–10560 (1992).

    CAS  PubMed  Google Scholar 

  33. Saadane, N., Alpert, L. & Chalifour, L.E. Altered molecular response to adrenoreceptor-induced cardiac hypertrophy in Egr-1-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 278, H796–H805 (2000).

    Article  CAS  Google Scholar 

  34. Livak, K.J. & Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402–408 (2001).

    Article  CAS  Google Scholar 

  35. Buvoli, M. & Leinwand, L.A. Direct gene transfer into mouse heart. Methods Enzymol. 346, 134–142 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

These studies were supported by grants from the Deutsche Forschungsgemeinschaft (Leibniz award), the Rudolf-Virchow-Center/DFG-Research Center for Experimental Biomedicine, the Bavarian Ministry of Technology, ProCorde and Sanofi-Aventis. We thank A. Simm (University of Halle) for advice on cardiomyocyte culture, C. Dienesch for help with aortic banding experiments and G. Thiel (University of Homburg) for the Egr-reporter gene construct and suggestions. We would like to thank P. Charnay for providing Egr1-deficient mice and L. Hein (University of Freiburg) for discussion of the manuscript.

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Authors and Affiliations

  1. Rudolf-Virchow-Center/DFG-Research Center for Experimental Biomedicine, University of Wuerzburg, Versbacher Strasse 9, Wuerzburg, 97078, Germany

    Monika Buitrago, Silke Oberdorf-Maass, Ursula Keller & Stefan Engelhardt

  2. Institute of Pharmacology and Toxicology, University of Wuerzburg, Versbacher Strasse 9, Wuerzburg, 97078, Germany

    Monika Buitrago, Kristina Lorenz, Eva M Schmitteckert & Martin J Lohse

  3. Medizinische Universitaetsklinik, University of Wuerzburg, Josef-Schneider-Strasse 2, Würzburg, 97080, Germany

    Alexander H Maass

  4. Cardiovascular Division, Sanofi-Aventis, Industriepark Höchst H823, Frankfurt am Main, 65926, Germany

    Yuri Ivashchenko

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  1. Monika Buitrago
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Correspondence to Stefan Engelhardt.

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Competing interests

Stegan Engelhardt, Monika Buitrago and Martin J. Lohse have filed a patent regarding the use of NAB/Egr in heart disease.

Supplementary information

Supplementary Table 1

Nab1 transgenic mice show normal cardiac function in vivo (PDF 16 kb)

Supplementary Methods (PDF 30 kb)

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Buitrago, M., Lorenz, K., Maass, A. et al. The transcriptional repressor Nab1 is a specific regulator of pathological cardiac hypertrophy. Nat Med 11, 837–844 (2005). https://doi.org/10.1038/nm1272

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