Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence

Nat Commun. 2015 Mar 9:6:6473. doi: 10.1038/ncomms7473.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Aging / metabolism*
  • Aging / pathology
  • Animals
  • Cardiomyopathy, Dilated / chemically induced
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / metabolism*
  • Cardiomyopathy, Dilated / pathology
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Embryo, Mammalian
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Developmental
  • Heart Failure / chemically induced
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Heart Failure / pathology
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Humans
  • Isoproterenol
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myocardial Contraction / genetics
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Paracrine Communication
  • Polycomb Repressive Complex 1 / genetics*
  • Polycomb Repressive Complex 1 / metabolism
  • Transcriptome

Substances

  • BMI1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Polycomb Repressive Complex 1
  • Isoproterenol