ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling

Koren, Lilach; Alishekevitz, Dror; Elhanani, Ofer; Nevelsky, A.; Hai, Tsonwin; Kehat, Izhak; Shaked, Yuval; Aronheim, Ami

doi:10.1016/j.ijcard.2015.06.099

Cited by 34 publications

(13 citation statements)

References 40 publications

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“…Also differentially expressed is E2F transcription factor 1 ( E2f1 , 2.9-fold, P = 3 × 10 −5 ), which is known to play a role in the cardiac stress response (18) and is an important downstream effector of TGFβ in cancer and various fibrotic diseases (19, 20). The cyclic-AMP dependent transcription factor Atf3 (7.4-fold, P = 2 × 10 −44 ), which promotes maladaptive cardiac remodeling and regulates cardiac fibrosis, was also upregulated in PLN R9C/+ (21, 22). …”

Section: Resultsmentioning

confidence: 99%

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

et al. 2016

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Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10−4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10−33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.

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Section: Resultsmentioning

confidence: 99%

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

et al. 2016

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“…Moreover, mice overexpressing the JDP2 homolog ATF3 also develop cardiac hypertrophy and dysfunction in absence of atrial defects 15 . In ATF3 mice, cardiomyocyte-macrophage cross talk seems to play a major role in the adverse cardiac effects of ATF3 16 . In our study we found induction of inflammatory marker genes in JDP2-overexpressing mice.…”

Section: Discussionmentioning

confidence: 99%

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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“…Alzet micro-osmotic pumps were used to achieve continuous administration of rmIL31 to mice for a period of 2 weeks, as previously described [47]. Briefly, C57Bl/6 tumor-bearing mice were subcutaneously implanted with micro-osmotic pumps (#1002, Alzet, Cupertino, CA) loaded with rmIL31 (at a dose of 0.7 μg/day) or PBS as a vehicle control.…”

Section: Methodsmentioning

confidence: 99%

The antiangiogenic role of the pro-inflammatory cytokine interleukin-31

Davidi¹,

Fremder²,

Kan³

et al. 2017

Oncotarget

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Pro-inflammatory cytokines in the tumor microenvironment are known for their ability to either inhibit or promote cancer progression. Here we evaluated the role of Interleukin-31 (IL31), a protein belonging to the pro-inflammatory IL-6 cytokine family which has been characterized in autoimmune disease, in tumorigenesis. We show that IL31 and its receptor, IL31RA, are highly expressed in various human and mouse cancer cell lines, as well as in tumor specimens from cancer patients. MC38 murine colon carcinoma cells depleted of IL31 exhibit an increase in invasive and migratory properties in vitro, effects that are reversed by supplementing the cells with exogenous IL31. In vivo, IL31-depleted MC38 tumor cells implanted to mice grow faster than control tumors. In contrast, MC38 tumor-bearing mice infused with recombinant IL31, exhibit a significant reduction in tumor growth than control mice. Furthermore, IL31 infusion reduces the number of metastatic lesions in the lungs of mice bearing 4T1 murine metastatic breast carcinoma. Lastly, injecting tumor-bearing, chemotherapy-treated mice with a long-lived IL31-IgG fusion protein reduces tumor growth, angiogenesis and pulmonary metastasis to a greater extent than when chemotherapy is used alone. The IL31 anti-tumor activity is explained, in part, by the anti-angiogenic effects demonstrated both in vitro and in vivo highlighting the potential use of IL31 as an anti-cancer drug.

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ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling

Cited by 34 publications

References 40 publications

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

JDP2 overexpression provokes cardiac dysfunction in mice

The antiangiogenic role of the pro-inflammatory cytokine interleukin-31

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