The AP-1 transcription factor c-Jun prevents stress-imposed maladaptive remodeling of the heart

PLoS One. 2013 Sep 10;8(9):e73294. doi: 10.1371/journal.pone.0073294. eCollection 2013.

Abstract

Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hypertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Gene Deletion
  • Heart / growth & development*
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Pressure
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Transcription Factor AP-1 / metabolism*

Substances

  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1

Grants and funding

This work was supported by the Roche Research Foundation and by the Swiss National Science Foundation SNSF (PP0033-114856). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.