The Role of Dual Loss-of-Function Mutations in the bZIP-Repressor Proteins, ATF3 and JDP2, in Cardiac Remodeling and Hypertrophy

The Activating Transcription Factor 3 (ATF3) and the c-Jun dimerization protein 2 (JDP2) are members of the basic leucine zipper protein (bZIP) superfamily of transcription factors. Both share a high degree of homology within the bZIP domain. Despite their high functional homology, the loss of JDP2 expression promotes, while ATF3 loss of expression prevents cardiac remodeling and hypertrophy. Interestingly, the loss of either ATF3 or JDP2 expression results in increased expression of the other gene. Therefore, we hypothesized that increased ATF3 expression in the absence of JDP2 results in a maladaptive cardiac response. To this end, mice with loss-of-function mutations in both ATF3 and JDP2 (double KO,) were generated.

Methods:

We used transverse aortic constriction (TAC) in C57Bl6 dKO and wild type (Wt) mice and assessed the cardiac physiological and molecular consequences at 4 and 8 weeks following TAC.

Results:

In the absence of cardiac stress, the hearts derived from dKO mice display a higher ventricles/body weight ratio (4.4) and superior cardiac function in comparison to Wt (3.7). Following 4 weeks of TAC, dKO hearts remained fully functional while Wt mice exhibited reduced cardiac function. Following 8 weeks of TAC, all mice showed deterioration in cardiac function. However, dKO mice exhibited preserved systolic function (EF: 53%), in comparison to Wt mice (EF: 37%). Consistently, the hearts of Wt mice showed significant elevation in hypertrophic, fibrosis, and inflammatory cytokine gene markers in comparison to dKO following TAC. Consistent with previous studies suggesting an adaptive role of p38 activity in TAC-induced cardiac hypertrophy, we found an increased phospho-p38 activity in both control and following 8 weeks of TAC in dKO mice compered to Wt mice.

Conclusion:

ATF3 and JDP2 dual ablation has a beneficial outcome to heart function. Hearts derived from dKO mice display amelioration in contractile function in the absence of stress; and are resistant to maladaptive cardiac remodeling processes with preserved contractile function following chronic pressure overload model.