Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence.
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 p16(INK4a) derepression, accompanied by a senescence-associated secretory phenotype (SASP), is linked to severely impaired ventricular dimensions and contractility. Genetic reduction of p16(INK4a) 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.
Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
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I
Gonzalez-Valdes
Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
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I
Hidalgo
Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
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A
Bujarrabal
Molecular Regulation of Heart Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
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E
Lara-Pezzi
1] Molecular Regulation of Heart Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain [2] Heart Failure and Inherited Cardiac Diseases Unit, Hospital Universitario Puerta de Hierro Majadahonda, Manuel de Falla, 1, E-28222 Madrid, Spain.
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L
Padron-Barthe
Heart Failure and Inherited Cardiac Diseases Unit, Hospital Universitario Puerta de Hierro Majadahonda, Manuel de Falla, 1, E-28222 Madrid, Spain.
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P
Garcia-Pavia
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P
Gómez-del Arco
Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
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P
Gomez
Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
J M
JM
Redondo
Advanced Imaging Unit, Ciber de Enfermedades respiratorias and UCM, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
J M
JM
Ruiz-Cabello
Advanced Imaging Unit, Ciber de Enfermedades respiratorias and UCM, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
L J
LJ
Jimenez-Borreguero
Functional Genetics of the Oxidative Phosphorylation System, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
J A
JA
Enriquez
Intercellular Signaling In Cardiovascular Development and Disease Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
J L
JL
de la Pompa
Imaging the Cardiovascular Inflammation and the Immune Response, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
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A
Hidalgo
Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), E-28029 Madrid, Spain.
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S
Gonzalez
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D063150:Polycomb Repressive Complex 1; D007545:Isoproterenol