Article

Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence

  • Nature Communications 6, Article number: 6473 (2015)
  • doi:10.1038/ncomms7473
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Abstract

Dilated cardiomyopathy (DCM) is the most frequent cause of heart failure and the leading indication for heart transplantation. Here we show that epigenetic regulator and central transcriptional instructor in adult stem cells, Bmi1, protects against DCM by repressing cardiac senescence. Cardiac-specific Bmi1 deletion induces the development of DCM, which progresses to lung congestion and heart failure. In contrast, Bmi1 overexpression in the heart protects from hypertrophic stimuli. Transcriptome analysis of mouse and human DCM samples indicates that p16INK4a derepression, accompanied by a senescence-associated secretory phenotype (SASP), is linked to severely impaired ventricular dimensions and contractility. Genetic reduction of p16INK4a levels reverses the pathology of Bmi1-deficient hearts. In parabiosis assays, the paracrine senescence response underlying the DCM phenotype does not transmit to healthy mice. As senescence is implicated in tissue repair and the loss of regenerative potential in aging tissues, these findings suggest a source for cardiac rejuvenation.

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Change history

  • Updated online 07 March 2017

    This paper has been retracted at the request of the authors.

  • Updated online 14 May 2015

    In the original version of this Article, the last name of the author Pablo Gómez-del Arco was incorrectly given as Gomez, and the affiliation details were incorrect. This has now been corrected in both the PDF and HTML versions of the Article.

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Acknowledgements

We thank Miguel Torres and Jose Antonio Enriquez for helpful discussions; Rebeca Diges for excellent technical assistance; and Simon Bartlett for text editing. S.G. is funded by the Human Frontiers Science Program Organization and the Spanish Ministries of Economy and Competitiveness (SAF2010-15386 and SAF2013-42252-R). The CNIC is supported by the Ministery of Economy and Competitiveness and the Pro-CNIC Foundation.

Author information

Affiliations

  1. Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain

    • I. Gonzalez-Valdes
    • , I. Hidalgo
    • , A. Bujarrabal
    •  & S. Gonzalez
  2. Molecular Regulation of Heart Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain

    • E. Lara-Pezzi
    •  & L. Padron-Barthe
  3. Heart Failure and Inherited Cardiac Diseases Unit, Hospital Universitario Puerta de Hierro Majadahonda, Manuel de Falla, 1, E-28222 Madrid, Spain

    • L. Padron-Barthe
    •  & P. Garcia-Pavia
  4. Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain

    • Pablo Gómez-del Arco
    •  & J.M. Redondo
  5. Department of Molecular Biology, Universidad Autonoma de Madrid, E28049 Madrid, Spain

    • Pablo Gómez-del Arco
  6. Advanced Imaging Unit, Ciber de Enfermedades respiratorias and UCM, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain

    • J.M. Ruiz-Cabello
    •  & L.J. Jimenez-Borreguero
  7. Functional Genetics of the Oxidative Phosphorylation System, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain

    • J.A. Enriquez
  8. Intercellular Signaling In Cardiovascular Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain

    • J.L. de la Pompa
  9. Imaging the Cardiovascular Inflammation and the Immune Response, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain

    • A. Hidalgo

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Contributions

I.G.-V. has performed most of the experiments; I.H., L.P.-B., P.G., J.M.R. and A.B. have contributed to data analysis and discussion of the paper; J.M.R.-C., L.J.J.-B. have performed the imaging data; P.G.-P. and E.L.-P. have contributed with the samples of DCM patients; J.A.E., J.L.d.l.P. and A.H. have supervised the data analysis; S.G. designed and supervised the study and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to S. Gonzalez.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures and Supplementary Table

    Supplementary Figures 1-3 and Supplementary Table 1

Excel files

  1. 1.

    Supplementary Data 1

    The supplementary dataset shows 2435 genes differentially expressed between heart samples of dilated cardiomyopathy-diagnosed patients (who had undergone heart transplant; hDCM) and healthy control patients, as well as 649 genes differentially expressed from heart samples of Bmi1f/f;aMHCTM-Cretg/+ and controls mice (17 weeks postinduction; mDCM).

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