Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure

Mayer, Sandra C.; Gilsbach, Ralf; Preißl, Sebastian; Ordonez, Elsa Beatriz Monroy; Schnick, Tilman; Beetz, Nadine; Lother, Achim; Rommel, Carolin; Ihle, Hannah; Bugger, Heiko; Rühle, Frank; Schrepper, Andrea; Schwarzer, Michael; Heilmann, Claudia; Bönisch, Ulrike; Gupta, Shashi; Wilpert, Jochen; Kretz, Oliver; Elverfeldt, Dominik von; Orth, J.; Aktories, Klaus; Beyersdorf, Friedhelm; Bode, Christoph; Stiller, Brigitte; Krüger, Markus; Thum, Thomas; Doenst, Torsten; Stoll, Monika; Hein, Lutz

doi:10.1161/circresaha.115.306721

Cited by 62 publications

(40 citation statements)

References 38 publications

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“…Through GO term and PPI analyses, the dysregulated genes under TAC were recognized. As another article reported [15], MeCP2 was downregulated under TAC and restored under rTAC. Next, we screened and aligned the genes with the same Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry regulation trend as MeCP2 and the genes with the reverse regulation trends from MeCP2 under TAC and rTAC.…”

Section: Category and Group Of Datamentioning

confidence: 73%

“…The dataset contained 49 samples, including wild-type (WT), MeCP2-overexpressing (TG), and MeCP2-knockout (KO) mice; healthy mice (Sham) that underwent transverse aortic constriction (TAC); and mice that underwent removal of the aortic stenosis (reversible TAC, rTAC) [15].…”

Section: Initial Datasetsmentioning

confidence: 99%

“…In human and mouse heart failure, MeCP2 is repressed, and prevention of MeCP2 repression in mice after chronic cardiac pressure overload aggravates cardiac hypertrophy and mitochondrial and contractile dysfunction. In contrast, ablation of MeCP2 expression in cardiac myocytes in vivo facilitates functional recovery from cardiac failure by mechanical unloading of the heart [15]. It has also been reported that MeCP2-overexpressing human endothelial cells have impaired migration capacity and angiogenic activity, whereas MeCP2-silenced endothelial cells have improved endothelial migration and tube formation capacity [16].…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Mecp2 on Heart Failure

Wang

Cao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Heart failure is the end result of various kinds of cardiovascular diseases. It has a high rate of morbidity and mortality. This article aims to determine the effect of MeCP2, a key epigenetic regulator, on heart failure. Methods: The genes associated with heart failure were selected and analyzed using Gene Ontology (GO) term analysis and protein-protein interaction (PPI) network analysis. Significantly up- or downregulated genes in a heart failure animal model were identified, and the genes that had the same or opposite alteration trends as MeCP2 were also recognized. Eighteen hub genes were picked based on topological parameters, and then aberrantly expressed genes with MeCP2 overexpression or knockout were analyzed by GO term, KEGG pathway and PPI analyses. Results: MeCP2 was downregulated in the heart failure animal model. Through comparison and alignment, 10 dysregulated genes were selected from the 18 hub genes (JAK1, SETD1B, HRC, TTN, LYZ2, TPM3, MYH11, MYH6, ALOX5AP, DECR1). These genes were mainly enriched in cytoskeletal regulation mediated by Rho GTPase and inflammation mediated by chemokine and cytokine signaling pathways. Conclusions: These dysregulated genes provide a better understanding of the underlying mechanisms of the effect of MeCP2 on heart failure and might be used as targets and prognostic markers of heart failure.

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Section: Category and Group Of Datamentioning

confidence: 73%

Section: Initial Datasetsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Effect of Mecp2 on Heart Failure

Wang

Cao

et al. 2018

Cell Physiol Biochem

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“…12 Downregulation of MeCP2 by siRNA reduces apoptosis after ischemia, 13 and MeCP2 overexpression in heart can be embryonic lethal, 14 in agreement with the current study. 1 Overall, past work suggests that miR-132/212 induction and MeCP2 repression might be a general adaptive mechanism in the heart and other organs.…”

Section: Mirs-132/212 and Mecp2: Background And Supporting Datamentioning

confidence: 99%

“…Contrary to this paradigm, Lutz Hein’s group in this issue of Circulation Research provides evidence for a cardioprotective pathway mediated by activation of cardiac myocyte adrenergic receptors (ARs). 1 This novel pathway involves β1- and α1-ARs, miRs-132/212, and the epigenetic regulator, methyl CpG binding protein 2 (MeCP2), the X-linked gene mutated in Rett Syndrome, a neurological disorder. Figure 1 outlines the model, and the data from the paper that support it.…”

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confidence: 99%

A New Pathway for Sympathetic Cardioprotection in Heart Failure

Simpson

2015

Circulation Research

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Disrupting methyl‐CpG‐binding protein 2 expression induces the transformation of induced pluripotent stem cell cardiomyocytes into pacemaker‐like cells by insulin gene enhancer binding protein 1

Zhang

Shi

et al. 2023

The Journal of Gene Medicine

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Background The experiment will explore whether interfering with the expression of methyl‐CpG‐binding protein 2 (MecP2) can enhance the ability of insulin gene enhancer binding protein 1 (ISL1) to induce iPSC‐CMs to differentiate into pacemaker‐like cells. Methods Differentiation of induced pluripotent stem cells (iPSCs) into cardiomyocytes (CMs) can be induced via the regulation of the Wnt signaling pathway. Real‐time quantitative PCR (qPCR), western blotting, immunofluorescence staining, and patch‐clamp technique were used to analyze the ability of ISL1 to induce the transformation of iPSC‐CMs into pacemaker‐like cells. Calcium spark, patch‐clamp technique, and real‐time qPCR were used to verify whether disrupting the expression of MeCP2 enhanced this ability of ISL1 to induce the differentiation of iPSC‐CMs into pacemaker cells. Transplant pacemaker‐like cardiomyocytes into the myocardium of mice to observe whether the pacemaker cells can survive in the tissue for a long time. Results RT‐qPCR and patch‐clamp analyses showed that overexpression of ISL1 induced the successful differentiation of iPSC‐CMs into pacemaker cells. ISL1‐overexpressing pacemaker‐like cells possessed typical characteristics of pacemaker morphology, including action potential and If inward current. Chromatin immunoprecipitation results showed that MeCP2 bound to the promoter region of HCN4. Following disruption of MeCP2 expression, the gene expression of sinoatrial node‐specific transcription factors, If inward current, and cardiac rhythm changes in iPSC‐CMs resembled those of sinoatrial node pacemaker cells. Therefore, ISL1 induced the differentiation of iPSC‐CMs into pacemaker‐like cells, and knockdown of MeCP2 increased this effect. Frozen section results showed that surviving pacemaker‐like cells could still be observed in myocardial tissue after 45 days. Conclusions Experiments have found that interfering with the expression of MeCP2 can increase the ability of ISL1 to induce iPSC‐CM cells to differentiate into pacemaker‐like cells. And the pacemaker‐like cells obtained in this experiment can survive in myocardial tissue for a long time.

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Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure

Abstract: Supplemental Digital Content is available in the text.

Cited by 62 publications

References 38 publications

The Effect of Mecp2 on Heart Failure

The Effect of Mecp2 on Heart Failure

A New Pathway for Sympathetic Cardioprotection in Heart Failure

Disrupting methyl‐CpG‐binding protein 2 expression induces the transformation of induced pluripotent stem cell cardiomyocytes into pacemaker‐like cells by insulin gene enhancer binding protein 1

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