JDP2 and ATF3 — bZIP repressors in cardiac remodeling

Abstract

We thank Guo et al. for their letter to the editor entitled “JDP2: A novel therapeutic thought in cardiac remodeling”. JDP2 and ATF3 are two basic leucine zipper protein (bZIP) members of the AP-1 family of transcription factors. JDP2 and ATF3 share a high degree of homology within their bZIP domain and bind related TPA- and cAMP-response elements found in the promoter of numerous genes. JDP2 and ATF3 possess indistinguishable transcription repression activity [ [1] Darlyuk-Saadon I. Weidenfeld-Baranboim K. Yokoyama K.K. Hai T. Aronheim A. The bZIP repressor proteins, c-Jun dimerization protein 2 and activating transcription factor 3, recruit multiple HDAC members to the ATF3 promoter. Biochim. Biophys. Acta. 1819; 2012: 1142-1153 Google Scholar ]. ATF3 was found to be elevated in patients with heart failure [ [2] Zhou H. Shen D.F. Bian Z.Y. Zong J. Deng W. Zhang Y. et al. Activating transcription factor 3 deficiency promotes cardiac hypertrophy, dysfunction, and fibrosis induced by pressure overload. PLoS One. 2011; 6e26744 Crossref PubMed Scopus (65) Google Scholar ], however, whether the expression of ATF3 is adaptive or maladaptive is currently unknown. In mice, chronic pressure overload raises ATF3 expression which is correlated with maladaptive cardiac remodeling [ [3] Koren L. Alishekevitz D. Elhanani O. Nevelsky A. Hai T. Kehat I. et al. ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling. Int. J. Cardiol. 2015; 198: 232-240 Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar ]. Previously, we have shown that ATF3 transcription is suppressed by JDP2 [ [4] Weidenfeld-Baranboim K. Hasin T. Darlyuk I. Heinrich R. Elhanani O. Pan J. et al. The ubiquitously expressed bZIP inhibitor, JDP2, suppresses the transcription of its homologue immediate early gene counterpart, ATF3. Nucleic Acids Res. 2009; 37: 2194-2203 Crossref PubMed Scopus (36) Google Scholar ]. Interestingly, JDP2-KO mice exposed to eight weeks chronic pressure overload (transverse aortic constriction [TAC]), display increased ATF3 expression and deteriorated heart function. In addition, mice with ATF3-KO exhibit a partial beneficial cardiac outcome [ [5] Kalfon R. Haas T. Shofti R. Moskovitz J.D. Schwartz O. Suss-Toby E. et al. c-Jun dimerization protein 2 (JDP2) deficiency promotes cardiac hypertrophy and dysfunction in response to pressure overload. Int. J. Cardiol. 2017; 249: 357-363 Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar ]. In contrast, other studies suggested that ATF3 deficiency promotes maladaptive cardiac remodeling four weeks following TAC [ [2] Zhou H. Shen D.F. Bian Z.Y. Zong J. Deng W. Zhang Y. et al. Activating transcription factor 3 deficiency promotes cardiac hypertrophy, dysfunction, and fibrosis induced by pressure overload. PLoS One. 2011; 6e26744 Crossref PubMed Scopus (65) Google Scholar ]. Since cardiac growth was similar at the end point of the two studies, the distinct kinetics following TAC cannot provide an explanation for the opposing results. We do agree with Guo et al. that JDP2 can be thought of as a therapeutic target. Moreover, exploring the molecular mechanism involved in the differential activity of the two highly homologous transcription factors may provide understanding of how an adaptive cardiac remodeling process turns into a maladaptive outcome. JDP2: A novel therapeutic thought in cardiac remodelingInternational Journal of CardiologyVol. 257PreviewWe read with great interest the recently published paper by Kalfon, R and colleagues [1]. They discovered involvements of JDP2 during TAC-caused cardiac remodeling, and suggested that JDP2-null mice suffered from deteriorated hypertrophy, fibrosis and malfunction as a result of ATF3 activation through limiting p38MAPK pathway. Consistently, by employing cardiomyocytes with isoprenaline infusion, Hill et al. gave insights that JDP2 overexpression was capable to blunt hypertrophic response due to specific abrogation of AP-1 [2]. Full-Text PDF