c-Jun dimerization protein 2 (JDP2) deficiency promotes cardiac hypertrophy and dysfunction in response to pressure overload

Kalfon, Roy; Haas, Tali; Shofti, Rona; Moskovitz, Jacob D.; Schwartz, Ortal; Suss-Toby, Edith; Aronheim, Ami

doi:10.1016/j.ijcard.2017.08.074

Cited by 14 publications

(21 citation statements)

References 30 publications

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“…Quite puzzling to our findings of impaired cardiac function under JDP2 overexpression is the fact, that knock out of JDP2 also provokes cardiac dysfunction in response to pressure overload 11 . However, these findings might mirror the divergent actions of JDP2: On the transcriptional control of gene expression JDP2 acts as specific AP-1 inhibitor but also as modulator of chromatin remodeling.…”

Section: Discussioncontrasting

confidence: 61%

“…In the study of Kalfon et al . 11 JDP2 knock out mice basically presents normal cardiac function. Only after aortic constriction, stronger cardiac impairments became evident in JDP2 knock out mice compared to WT animals.…”

Section: Discussionmentioning

confidence: 96%

“…These results imply a protective role of JDP2 in heart failure, and the induction of JDP2 after myocardial infarction may be an adaptive process. Another argument for the protective role of JDP2 is the recent finding, that knock out of JDP2 promotes cardiac hypertrophy and dysfunction in response to pressure overload in mice 11 . However, besides these positive effects, JDP2 also has detrimental effects in cardiomyocytes, since the contractile function of ventricular cardiomyocytes isolated from JDP2-overexpressing mice was impaired: While wildtype cardiomyocytes showed enhanced cell shortening as well as faster contraction and relaxation velocities with increasing amounts of the beta adrenoceptor agonist isoprenaline, JDP2-overexpressing cells failed to respond to β-adrenergic stimulation 10 .…”

Section: Introductionmentioning

confidence: 99%

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JDP2 overexpression provokes cardiac dysfunction in mice

Heger

Bornbaum

Würfel

et al. 2018

Sci Rep

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The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiac function, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development.

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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JDP2 overexpression provokes cardiac dysfunction in mice

Heger

Bornbaum

Würfel

et al. 2018

Sci Rep

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“…Surprisingly, a loss-of-function approach showed an opposite adaptive role of JDP2. In a pressure overload model induced by Transverse Aortic Constriction (TAC), JDP2 KO mice performed worse than WT mice [14]. These results supported a protective role of JDP2, opposite from the expectation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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“…3C), some of which playing pivotal roles in heart development. As the case of Iroquois homeobox gene 1 (Irx1), encoding a cardiac transcription factor important for the development of ventricular conduction system 20 ; Krüppel-like factor 5 (Klf5), a zinc finger-containing transcription factor involved in many different cellular processes, ranging from the governance of pluripotency of embryonic stem cell to regulation of cardiovascular pathophysiology [21][22][23] ; the transcriptional modulator Cited2, involved in Brachyury, Mesp1, Isl1, Gata4 and Tbx5 expression during cardiac differentiation of embryonic stem cells 24 ; Nuclear receptor subfamily 4, group A, member 2 (NR4A2), also known as Nurr1, a member of the NR4A orphan nucleus receptor family involved in the immediate early response to different stress-stimuli, with some roles in cardiac remodelling 25 ; Tbx6, a member of the evolutionarily conserved T-box family of transcription factors that are essential regulators of normal embryonic development, critical for mesoderm induction and subsequent lineage diversification by regulation of Nkx2-5 expression 26 ; JMJD2A/KDM4A, a member of the JmjC domain-containing family JMJD2 of histone demethylases that catalyse the demethylation of trimethylated H3K9 (H3K9me3) and H3K36 (H3K36me3), involved in promotion of cardiac hypertrophy 27 , as well as the c-Jun dimerization protein 2, JDP2, member of the basic leucine zipper (bZIP) superfamily which typically suppresses transcription through binding to CRE and TRE DNA promoter elements and recruiting histone deacetylases 28 ; Rp58 (also known Znf238, Zfp238, Zbtb18), a sequence-specific transcriptional repressor which inhibits Id genes (Id1-4) playing a central and evolutionarily conserved role during muscle formation 29 ; the ubiquitous protein PHF10, a subunit of the PBAF chromatin-remodelling complexes which plays crucial role in antagonizing Polycomb action during development 30 ; the forkhead box transcription factors Foxd1, which has been recently described as a promoter of iPSC generation 31 ; the myocyte-specific enhancer factor MEF2b 32 .…”

Section: Ptc-209 Pre-treatment Modulates Signalling Pathways Governinmentioning

confidence: 99%

Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes

Testa

Russo

Benedetto

et al. 2020

Sci Rep

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The development of therapeutic approaches based on direct cardiac reprogramming of fibroblasts into induced-cardiomyocytes (iCM) has emerged as an attractive strategy to repair the injured myocardium. The identification of the mechanisms driving lineage conversion represents a crucial step toward the development of new and more efficient regenerative strategies. To this aim, here we show that pretreatment with the Bmi1 inhibitor PTC-209 is sufficient to increase the efficiency of Chemical-induced Direct Cardiac Reprogramming both in mouse embryonic fibroblasts and adult cardiac fibroblasts. PTC-209 induces an overall increase of spontaneously beating iCM at end-stage of reprogramming, expressing high levels of late cardiac markers Troponin T and myosin muscle light chain-2v. The inhibition of Bmi1 expression occurring upon PTC-209 pre-treatment was maintained throughout the reprogramming protocol, contributing to a significant gene expression de-regulation. RNA profiling revealed that, upon Bmi1 inhibition a significant down-regulation of genes associated with immune and inflammatory signalling pathways occurred, with repression of different genes involved in interleukin, cytokine and chemokine pathways. Accordingly, we observed the down-regulation of both JAK/STAT3 and MAPK/ERK1-2 pathway activation, highlighting the crucial role of these pathways as a barrier for cardiac reprogramming. These findings have significant implications for the development of new cardiac regenerative therapies.

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c-Jun dimerization protein 2 (JDP2) deficiency promotes cardiac hypertrophy and dysfunction in response to pressure overload

Cited by 14 publications

References 30 publications

JDP2 overexpression provokes cardiac dysfunction in mice

JDP2 overexpression provokes cardiac dysfunction in mice

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

Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes

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