Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

Maier, Harald J.; Schips, Tobias G.; Wietelmann, Astrid; Krüger, Marcus; Brunner, Cornelia; Sauter, Martina; Klingel, Karin; Böttger, T; Braun, Thomas; Wirth, Thomas

doi:10.1073/pnas.1116584109

Cited by 161 publications

(126 citation statements)

References 30 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Studies in animal models have linked several master TFs (Gata4, c-Myc, Nfat3, NF-κB) to the induction of pathological gene sets that leads to the development of HF (14,(29)(30)(31). Moreover, physical exercise also highly influences cardiac function through increases in expression of these specific gene sets (32).…”

Section: Discussionmentioning

confidence: 99%

p53 regulates the cardiac transcriptome

Mak

Hauck

Grothe

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP–mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

p53 regulates the cardiac transcriptome

Mak

Hauck

Grothe

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

show abstract

“…For example, early inhibition of Stat3 can promote satellite muscle cell expansion, but prolonged inhibition impairs regeneration by limiting progenitor cell differentiation (47). Similarly, prolonged NF-κB activity may be maladaptive for the mammalian heart by promoting cardiomyocyte atrophy and fetal reprogramming of cardiomyocytes (22). Ultimately, the different physiologic states of zebrafish and mammalian hearts may contribute to differential NF-κB signaling with injury.…”

Section: Discussionmentioning

confidence: 99%

“…Since then, NF-κB signaling has been shown to have broad effects in a variety of tissues, influencing cell survival, tissue growth and proliferation, and chromatin structure (21). In the heart, NF-κB signaling has been implicated as a hypertrophic influence and has been linked to expression of cardiac response genes like ANF and β-MHC (22)(23)(24). Classically, NF-κB factors are sequestered in the cytoplasm through interaction with IκB.…”

mentioning

confidence: 99%

Myocardial NF-κB activation is essential for zebrafish heart regeneration

Karra

Knecht

Kikuchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.heart regeneration | cardiomyocyte | zebrafish | NF-κB | epicardium

show abstract

“…Further evidence supporting the cytokine hypothesis is derived from various transgenic and knockout animal models. They convincingly demonstrate that the over expression or mutation of a single cytokine/ chemokine/growth factor, a corresponding receptor or intracellular signalling molecule is sufficient to evoke HF [5][6][7]. However, these signalling cascades are not detrimental per se but constitute an evolutionary conserved defence mechanism [6,8,9].…”

Section: Introductionmentioning

confidence: 99%

Oncostatin M Induces FGF23 Expression in Cardiomyocytes

Richter¹,

Polyakova²,

Gajawada³

2012

J Clin Exp Cardiolog

View full text Add to dashboard Cite

Background: It is well-known that elevated levels of Fibroblast Growth Factor-23 (FGF23), a bone derived hormone, in circulation are associated with renal failure. Recent studies emphasize the correlation between Heart Failure (HF) and FGF23, but the ability of cardiomyocytes themselves to express and secrete this phosphatonin is yet unknown. A further factor involved in HF is the cytokine oncostatin M (OSM). The aims of our study were: 1) to analyze the myocardium of HF patients in terms of FGF23 expression in cardiomyocytes and 2) to assess whether OSM is able to induce FGF23 production in cardiomyocytes. Methods:Cultures of adult cardiomyocytes were treated with OSM and screened for the expression of FGF23 transcripts. FGF23 secretion was determined by Western blot and ELISA of cell culture supernatants. Heart explants of HF patients with Dilated Cardiomyopathy (DCM), Ischemic Cardiomyopathy (ICM) and myocarditis (Myo) were analyzed by immunofluorescence using FGF23 antibodies and compared with healthy controls. FGF23 levels were also determined in mice with a cardiac restricted overexpression of Monocyte Chemotactic Protein-1 (MCP1), which developed an "inflammatory" Heart Failure (iHF) due to macrophage infiltration.Results: OSM massively induced the expression and secretion of FGF23 in cultured adult cardiomyocytes. Confocal microscopy revealed high amounts of FGF23 positive cardiomyocytes in the myocardium of patients with ischemic heart disease (IHD), myocarditis, dilated cardiomyopathy (DCM) and in mice with iHF. Conclusions:The presence of FGF23 in the myocardium of patients with different types of HF and in mice with "inflammatory" HF suggests that macrophages are responsible for the FGF23 expression in cardiomyocytes via OSM. Whether FGF23 acts as a regeneration promoting factor and/or potentially serves as a HF/transplantation marker has to be clarified.

show abstract

Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure

Cited by 161 publications

References 30 publications

p53 regulates the cardiac transcriptome

p53 regulates the cardiac transcriptome

Myocardial NF-κB activation is essential for zebrafish heart regeneration

Oncostatin M Induces FGF23 Expression in Cardiomyocytes

Contact Info

Product

Resources

About