Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence

I. Gonzalez-Valdes, I. Hidalgo, A. Bujarrabal, E. Lara-Pezzi, L. Padron-Barthe, P. Garcia-Pavia, Pablo Gómez-del Arco, J.M. Redondo, J.M. Ruiz-Cabello, L.J. Jimenez-Borreguero, J.A. Enriquez, J.L. de la Pompa, A. Hidalgo and S. Gonzalez ()
Additional contact information
I. Gonzalez-Valdes: Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
I. Hidalgo: Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
A. Bujarrabal: Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
E. Lara-Pezzi: Molecular Regulation of Heart Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
L. Padron-Barthe: Molecular Regulation of Heart Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
P. Garcia-Pavia: Heart Failure and Inherited Cardiac Diseases Unit, Hospital Universitario Puerta de Hierro Majadahonda
Pablo Gómez-del Arco: Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
J.M. Redondo: Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
J.M. Ruiz-Cabello: Advanced Imaging Unit, Ciber de Enfermedades respiratorias and UCM, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
L.J. Jimenez-Borreguero: Advanced Imaging Unit, Ciber de Enfermedades respiratorias and UCM, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
J.A. Enriquez: Functional Genetics of the Oxidative Phosphorylation System, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
J.L. de la Pompa: Intercellular Signaling In Cardiovascular Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
A. Hidalgo: Imaging the Cardiovascular Inflammation and the Immune Response, Centro Nacional de Investigaciones Cardiovasculares (CNIC)
S. Gonzalez: Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC)

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7473

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