JDP2 and ATF3 deficiencies dampen maladaptive cardiac remodeling and preserve cardiac function

PLoS One. 2019 Feb 28;14(2):e0213081. doi: 10.1371/journal.pone.0213081. eCollection 2019.

Abstract

c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / deficiency*
  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / physiology
  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Female
  • Fibrosis
  • Heart / physiopathology
  • Inflammation Mediators / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myocardial Contraction / genetics
  • Myocardial Contraction / physiology
  • Myocardium / pathology
  • Repressor Proteins / deficiency*
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology
  • Ventricular Remodeling / genetics
  • Ventricular Remodeling / physiology*

Substances

  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Inflammation Mediators
  • Jundp2 protein, mouse
  • Repressor Proteins

Grant support

This work was supported by AA Israel Science Foundation 731/17, https://www.isf.org.il/#/; AA Jess & Mildred Fisher Fund for Cardiology Research, Technion internal funds, AA TH USA-Israel Bi National grant 2015139, http://www.bsf.org.il/BSFPublic/Default.aspx; TF Rambam-Atidim academic excellence program, https://www.facebook.com/pg/RambamHCC/photos/?tab=album&album_id=407044016037532. None of the agencies mentioned above played any role in study design data collection analysis decision to publish or preparation of the manuscript.