Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy

In this study, we investigated the role of DNA methylation [5-methylcytosine (5mC)] and 5-hydroxymethylcytosine (5hmC), epigenetic modifications that regulate gene activity, in dilated cardiomyopathy (DCM). A MYBPC3 mutant mouse model of DCM was compared with wild type and used to profile genomic 5mC and 5hmC changes by Chip-seq, and gene expression levels were analyzed by RNA-seq. Both 5mC-altered genes (957) and 5hmC-altered genes (2,022) were identified in DCM hearts. Diverse gene ontology and KEGG pathways were enriched for DCM phenotypes, such as inflammation, tissue fibrosis, cell death, cardiac remodeling, cardiomyocyte growth, and differentiation, as well as sarcomere structure. Hierarchical clustering of mapped genes affected by 5mC and 5hmC clearly differentiated DCM from wild-type phenotype. Based on these data, we propose that genomewide 5mC and 5hmC contents may play a major role in DCM pathogenesis. NEW & NOTEWORTHY Our data demonstrate that development of dilated cardiomyopathy in mice is associated with significant epigenetic changes, specifically in intronic regions, which, when combined with gene expression profiling data, highlight key signaling pathways involved in pathological cardiac remodeling and heart contractile dysfunction.

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Reverse cardiac remodeling in patients with dilated cardiomyopathy post Cardiac Resynchronization Therapy (CRT) and its clinical implication

Benha Journal of Applied Sciences ◽

10.21608/bjas.2021.188843 ◽

2021 ◽

Vol 6 (3) ◽

pp. 195-205

Author(s):

K.E. El Rabat ◽

A. El Naggar ◽

S.I. Farag ◽

A.M. Heikal

Keyword(s):

Cardiac Resynchronization Therapy ◽

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Clinical Implication ◽

Cardiac Resynchronization ◽

Resynchronization Therapy ◽

Reverse Cardiac Remodeling

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Voluntary Exercise Improves Cardiac Function and Prevents Cardiac Remodeling in a Mouse Model of Dilated Cardiomyopathy

Frontiers in Physiology ◽

10.3389/fphys.2017.00899 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 7

Author(s):

Robin Deloux ◽

Damien Vitiello ◽

Nathalie Mougenot ◽

Philippe Noirez ◽

Zhenlin Li ◽

...

Keyword(s):

Mouse Model ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Voluntary Exercise

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Induction of Ankrd1 in Dilated Cardiomyopathy Correlates with the Heart Failure Progression

BioMed Research International ◽

10.1155/2015/273936 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Julius Bogomolovas ◽

Kathrin Brohm ◽

Jelena Čelutkienė ◽

Giedrė Balčiūnaitė ◽

Daiva Bironaitė ◽

...

Keyword(s):

Heart Failure ◽

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Expression Patterns ◽

Clinical Manifestations ◽

Left Ventricular ◽

Idiopathic Dilated Cardiomyopathy ◽

Expression Levels ◽

Potential Marker ◽

End Stage

Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands (ANKRD1,ANKRD2,TRIM63,TRIM55,NBR1,MLP,FHL2, andTCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevatedANKRD1expression levels marked transition from NYHA < IV to NYHA IV.ANKRD1expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardialANKRD1and serum adiponectin correlated with lowBAX/BCL-2ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM.ANKRD1expression correlated with reduced cardiac contractility and compliance. The association ofANKRD1with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure.

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In Vivo Delivery of Adenoviral Vector Containing Interleukin-17 Receptor A Reduces Cardiac Remodeling and Improves Myocardial Function in Viral Myocarditis Leading to Dilated Cardiomyopathy

PLoS ONE ◽

10.1371/journal.pone.0072158 ◽

2013 ◽

Vol 8 (8) ◽

pp. e72158 ◽

Cited By ~ 14

Author(s):

Yuquan Xie ◽

Minghui Li ◽

Xinggang Wang ◽

Xian Zhang ◽

Tianqing Peng ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Adenoviral Vector ◽

Myocardial Function ◽

Viral Myocarditis ◽

Interleukin 17 ◽

In Vivo Delivery

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Human Lysyl Oxidase Over-Expression Enhances Baseline Cardiac Oxidative Stress but Does Not Aggravate ROS Generation or Infarct Size Following Myocardial Ischemia-Reperfusion

Antioxidants ◽

10.3390/antiox11010075 ◽

2021 ◽

Vol 11 (1) ◽

pp. 75

Author(s):

Laura Valls-Lacalle ◽

Lídia Puertas-Umbert ◽

Saray Varona ◽

José Martínez-González ◽

Cristina Rodríguez ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Infarct Size ◽

Cardiac Remodeling ◽

Lysyl Oxidase ◽

Ischemia Reperfusion ◽

Ros Production ◽

Over Expression ◽

Myocardial Oxidative Stress ◽

Myocardial Ischemia Reperfusion

Lysyl oxidase (LOX) is an enzyme critically involved in collagen maturation, whose activity releases H2O2 as a by-product. Previous studies demonstrated that LOX over-expression enhances reactive oxygen species (ROS) production and exacerbates cardiac remodeling induced by pressure overload. However, whether LOX influences acute myocardial infarction and post-infarct left ventricular remodeling and the contribution of LOX to myocardial oxidative stress following ischemia-reperfusion have not been analyzed. Isolated hearts from transgenic mice over-expressing human LOX in the heart (TgLOX) and wild-type (WT) littermates were subjected to global ischemia and reperfusion. Although under basal conditions LOX transgenesis is associated with higher cardiac superoxide levels than WT mice, no differences in ROS production were detected in ischemic hearts and a comparable acute ischemia-reperfusion injury was observed (infarct size: 56.24 ± 9.44 vs. 48.63 ± 2.99% of cardiac weight in WT and TgLOX, respectively). Further, similar changes in cardiac dimensions and function were observed in TgLOX and WT mice 28 days after myocardial infarction induced by transient left anterior descending (LAD) coronary artery occlusion, and no differences in scar area were detected (20.29 ± 3.10 vs. 21.83 ± 2.83% of left ventricle). Our data evidence that, although LOX transgenesis induces baseline myocardial oxidative stress, neither ROS production, infarct size, nor post-infarction cardiac remodeling were exacerbated following myocardial ischemia-reperfusion.

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Overexpression of Heat Shock Protein 70 Improves Cardiac Remodeling and Survival in Protein Phosphatase 2A-Expressing Transgenic Mice with Chronic Heart Failure

Cells ◽

10.3390/cells10113180 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3180

Author(s):

Somy Yoon ◽

Ulrich Gergs ◽

Julie R. McMullen ◽

Gwang Hyeon Eom

Keyword(s):

Heart Failure ◽

Heat Shock ◽

Transgenic Mice ◽

Heat Shock Protein ◽

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Protein Phosphatase ◽

Postnatal Life ◽

Free Wall ◽

Wall Thinning

Heat shock protein (HSP) 70 is a molecular chaperone that regulates protein structure in response to thermal stress. In addition, HSP70 is involved in post-translational modification and is related to the severity of some diseases. Here, we tested the functional relevance of long-lasting HSP70 expression in a model of nonischemic heart failure using protein phosphatase 2 catalytic subunit A (PP2CA)-expressing transgenic mice. These transgenic mice, with cardiac-specific overexpression of PP2CA, abruptly died after 12 weeks of postnatal life. Serial echocardiograms to assess cardiac function revealed that the ejection fraction (EF) was gradually decreased in transgenic PP2CA (TgPP2CA) mice. In addition, PP2CA expression exacerbated systolic dysfunction and LV dilatation, with free wall thinning, which are indicators of fatal dilated cardiomyopathy. Interestingly, simultaneous expression of HSP70 in double transgenic mice (dTg) significantly improved the dilated cardiomyopathy phenotype of TgPP2CA mice. We observed better survival, preserved EF, reduced chamber enlargement, and suppression of free wall thinning. In the proposed molecular mechanism, HSP70 preferentially regulates the phosphorylation of AKT. Phosphorylation of AKT was significantly reduced in TgPP2CA mice but was not significantly lower in dTg mice. Signal crosstalk between AKT and its substrates, in association with HSP70, might be a useful intervention for patients with nonischemic heart failure to suppress cardiac remodeling and improve survival.

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