Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence

Nature Communications
I Gonzalez-ValdesS Gonzalez

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.

References

Jan 10, 2002·Genesis : the Journal of Genetics and Development·K A MosesR J Schwartz
Mar 1, 2003·Science·Joachim P SchmittChristine E Seidman
Nov 19, 2004·Nature·Scott W LoweGerard Evan
Jun 21, 2005·Genes & Development·Sophia W M BruggemanMaarten van Lohuizen
Mar 31, 2006·Nature·Susana GonzalezManuel Serrano
Jul 31, 2007·Cell·Manuel ColladoManuel Serrano
Aug 24, 2007·Nature·Paul KrimpenfortAnton Berns
Nov 6, 2007·The Journal of Physiological Sciences : JPS·Takao Shioya
Aug 23, 2008·Cell Cycle·Susana GonzalezManuel Serrano
Aug 30, 2008·Cell·Valery KrizhanovskyScott W Lowe
Apr 21, 2009·Journal of Molecular and Cellular Cardiology·Ross A BreckenridgeTimothy J Mohun
Oct 24, 2009·Nature Reviews. Cancer·Adrian P Bracken, Kristian Helin
Dec 30, 2009·The Journal of Clinical Investigation·Norifumi TakedaRyozo Nagai
Jan 19, 2010·Annual Review of Pathology·Jean-Philippe CoppéJudith Campisi
Aug 17, 2010·Nature Genetics·Sarah B NgJay Shendure
Sep 2, 2010·Cell Stem Cell·Martin Sauvageau, Guy Sauvageau
Nov 17, 2010·Genes & Development·Thomas KuilmanDaniel S Peeper
Nov 26, 2010·Current Opinion in Genetics & Development·Judith Campisi
Aug 10, 2011·The Journal of Cell Biology·Pamela A Harvey, Leslie A Leinwand
Nov 1, 2011·Annual Review of Physiology·Ching-Pin Chang, Benoit G Bruneau
Feb 4, 2012·Circulation Research·Gergana Dobreva, Thomas Braun
Apr 14, 2012·Circulation Research·Brian J North, David A Sinclair
Jan 3, 2013·The Journal of Clinical Investigation·Elizabeth M McNallyMegan J Puckelwartz
Jun 19, 2013·Nature Cell Biology·Juan Carlos AcostaJesús Gil
Jul 10, 2013·Nature Medicine·Russell C Addis, Jonathan A Epstein
Oct 8, 2013·Nature Structural & Molecular Biology·Luciano Di Croce, Kristian Helin
Jan 23, 2014·Genes & Development·Rafik SalamaMasashi Narita

❮ Previous
Next ❯

Citations

Oct 19, 2017·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Qi HuangXiangmei Chen
Oct 28, 2015·Stem Cell Research & Therapy·Iñigo Valiente-AlandiAntonio Bernad
May 14, 2016·Circulation Research·Akihiro ShirakabeJunichi Sadoshima
Dec 28, 2018·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Amiya Kumar GhoshRaymond Yung
Mar 30, 2016·Current Opinion in Cardiology·Soo Young KimJoseph A Hill

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE64391

Methods Mentioned

BETA
ubiquitination
genotyping
immunoprecipitation
ChIP
PCR
flow cytometry
RNAseq

Software Mentioned

FlowJo softwarem
ImageJ

Related Concepts

Related Feeds

Aging Genetics (Keystone)

This feed focuses on aging epidemiology and genetic, epigenetic, and proteomic aspects underlying aging, as well as aging- associated biomarkers. Here the latest research in this domain.

Adult Stem Cells

Adult stem cells reside in unique niches that provide vital cues for their survival, self-renewal, and differentiation. They hold great promise for use in tissue repair and regeneration as a novel therapeutic strategies. Here is the latest research.

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.

Cancer Epigenetics and Senescence (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may be involved in regulating senescence in cancer cells. This feed captures the latest research on cancer epigenetics and senescence.

Cardiac Regeneration

Cardiac regeneration enables the repair of irreversibly damaged heart tissue using cutting-edge science, including stem cell and cell-free therapy. Discover the latest research on cardiac regeneration here.

Genetics & Epigenetics of Aging

Dozens of genes are implicated in lifespan, and epigenetic changes during aging affect cell function. This feed focuses on the genetics and epigenetics of aging.