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

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.

ATF3 expression in cardiomyocytes and myofibroblasts following transverse aortic constriction displays distinct phenotypes

“…Cardiac MRI was performed to measure cardiac function and determine the severity of the TAC surgery. Details of the MRI and all other related experimental methods were described previously [12] , [15] . EF was calculated as follows: EF (%) = [(LVEDV- LVESV)/ LVEDV] × 100.…”

Tumor growth ameliorates cardiac dysfunction

“…how tumor progression affects the heart outcome. While studying the effect of cardiac remodeling on cancer, we noticed that tumor-bearing mice display improved cardiac outcome 9 as compared with cardiac remodeling processes obtained in non-tumor bearing mice 24 . This fact prompted us to set experiments directed to examine how tumor growth affects cardiac remodeling.…”

Novel and Annotated Long Noncoding RNAs Associated with Ischemia in the Human Heart

“…FEM1A is localized within mitochondria of cardiac muscle, is increased after myocardial infarction in mice [ 13 ] and may regulate apoptosis [ 14 ]. The second lncRNA hub, AAF111167.2, is antisense to, and overlaps the promoter of, JDP2, a transcription factor associated with maladaptive cardiac remodelling [ 15 ], whereas the third lncRNA hub, CTBP1-DT, is antisense to a transcriptional repressor, C-terminal-binding protein 1(CTBP1), which is involved in cell proliferation [ 16 ]. Several of the protein-coding genes in Module 1 have already been demonstrated to be associated with cardiac energy metabolism and apoptosis such as 2-oxoglutarate dehydrogenase (OGDH), a potent source of reactive oxygen species (ROS) in cardiac mitochondria [ 17 ].…”