Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Epigenetic Mechanisms of Cardiac Disease

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 32371

Share This Special Issue

Special Issue Editor

Prof. Dr. Ralph Knöll

E-Mail Website
Guest Editor

1. Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
2. ICMC (Integrated Cardio Metabolic Centre), Myocardial Genetics, Karolinska Institutet, University Hospital, Dept. of Medicine, Heart and Vascular Theme, Novum, Hiss A, våning 7, Hälsovägen 7-9, 141 57 Huddinge, Sweden
Interests: genetics; heart failure; epigenetics; molecular mechanisms
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite major breakthroughs in molecular biology and significant improvements in clinical medicine, heart failure remains a major cause of death worldwide. While in 30%–50% of individuals with heart failure, a genetic basis can be identified, and while fundamental molecular mechanisms, including hypertrophic signaling and a calcium metabolism, have been unraveled, our understanding of heart failure remains incomplete.

In this context, recent successful clinical trials point to the importance of sophisticated exploitation of already known signal transduction pathways, inflammation, and the need to explore even more novel biology and take interdisciplinary approaches to improve patients’ lives, for example, through SGLT2 inhibitors and diabeto-cardiology.

Along these lines and apart from genetics, epigenetics (“epi-” means above in Greek), which is defined as inheritable DNA modifications that do not change the DNA sequence, but which can affect gene activity, might play a role. These changes can be direct, for example, via genomic DNA methylations, or indirect via DNA interacting molecules such as histones or via miRNAs or similar.

In summary, genetic and epigenetic mechanisms are likely to operate in heart failure, the unraveling of which will undoubtedly lead to the improvement of patients’ lives.

In this issue, we will have a wide variety of papers looking at different aspects of epigenetic mechanisms underlying heart failure.

Dr. Ralph Knöll
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

epigenetics
genetics
heart failure
cardiomyopathy
molecular mechanisms
genomic DNA methylation
miRNAs
histone modifications

Published Papers (10 papers)

Download All Papers

Research

Jump to: Review

12 pages, 1021 KiB

Open AccessArticle

Differential Methylation in the GSTT1 Regulatory Region in Sudden Unexplained Death and Sudden Unexpected Death in Epilepsy

by Steffan Noe Christiansen, Stine Bøttcher Jacobsen, Jeppe Dyrberg Andersen, Marie-Louise Kampmann, Linea Christine Trudsø, Kristine Boisen Olsen, Jacob Tfelt-Hansen, Jytte Banner and Niels Morling

Int. J. Mol. Sci. 2021, 22(6), 2790; https://doi.org/10.3390/ijms22062790 - 10 Mar 2021

Cited by 5 | Viewed by 2332

Abstract

Sudden cardiac death (SCD) is a diagnostic challenge in forensic medicine. In a relatively large proportion of the SCDs, the deaths remain unexplained after autopsy. This challenge is likely caused by unknown disease mechanisms. Changes in DNA methylation have been associated with several heart diseases, but the role of DNA methylation in SCD is unknown. In this study, we investigated DNA methylation in two SCD subtypes, sudden unexplained death (SUD) and sudden unexpected death in epilepsy (SUDEP). We assessed DNA methylation of more than 850,000 positions in cardiac tissue from nine SUD and 14 SUDEP cases using the Illumina Infinium MethylationEPIC BeadChip. In total, six differently methylated regions (DMRs) between the SUD and SUDEP cases were identified. The DMRs were located in proximity to or overlapping genes encoding proteins that are a part of the glutathione S-transferase (GST) superfamily. Whole genome sequencing (WGS) showed that the DNA methylation alterations were not caused by genetic changes, while whole transcriptome sequencing (WTS) showed that DNA methylation was associated with expression levels of the GSTT1 gene. In conclusion, our results indicate that cardiac DNA methylation is similar in SUD and SUDEP, but with regional differential methylation in proximity to GST genes. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

16 pages, 2647 KiB

Open AccessArticle

Epigenetic Changes Governing Scn5a Expression in Denervated Skeletal Muscle

by David Carreras, Rebecca Martinez-Moreno, Mel·lina Pinsach-Abuin, Manel M. Santafe, Pol Gomà, Ramon Brugada, Fabiana S. Scornik, Guillermo J. Pérez and Sara Pagans

Int. J. Mol. Sci. 2021, 22(5), 2755; https://doi.org/10.3390/ijms22052755 - 09 Mar 2021

Cited by 4 | Viewed by 2503

Abstract

The SCN5A gene encodes the α-subunit of the voltage-gated cardiac sodium channel (Na_V1.5), a key player in cardiac action potential depolarization. Genetic variants in protein-coding regions of the human SCN5A have been largely associated with inherited cardiac arrhythmias. Increasing evidence also suggests that aberrant expression of the SCN5A gene could increase susceptibility to arrhythmogenic diseases, but the mechanisms governing SCN5A expression are not yet well understood. To gain insights into the molecular basis of SCN5A gene regulation, we used rat gastrocnemius muscle four days following denervation, a process well known to stimulate Scn5a expression. Our results show that denervation of rat skeletal muscle induces the expression of the adult cardiac Scn5a isoform. RNA-seq experiments reveal that denervation leads to significant changes in the transcriptome, with Scn5a amongst the fifty top upregulated genes. Consistent with this increase in expression, ChIP-qPCR assays show enrichment of H3K27ac and H3K4me3 and binding of the transcription factor Gata4 near the Scn5a promoter region. Also, Gata4 mRNA levels are significantly induced upon denervation. Genome-wide analysis of H3K27ac by ChIP-seq suggest that a super enhancer recently described to regulate Scn5a in cardiac tissue is activated in response to denervation. Altogether, our experiments reveal that similar mechanisms regulate the expression of Scn5a in denervated muscle and cardiac tissue, suggesting a conserved pathway for SCN5A expression among striated muscles. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

16 pages, 2564 KiB

Open AccessArticle

Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms

by Min Young Park, Bala Murali Krishna Vasamsetti, Wan Seop Kim, Hee Jung Kang, Do-Young Kim, Byeonghwi Lim, Kahee Cho, Jun Seok Kim, Hyun Keun Chee, Jung Hwan Park, Hyun Suk Yang, Harikrishna Reddy Rallabandi, Sun A. Ock, Mi-Ryung Park, Heasun Lee, In-Sul Hwang, Jun-Mo Kim, Keon Bong Oh and Ik Jin Yun

Int. J. Mol. Sci. 2021, 22(2), 751; https://doi.org/10.3390/ijms22020751 - 13 Jan 2021

Cited by 8 | Viewed by 3028

Abstract

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey’s blood parameters were analyzed on days −7, −3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

27 pages, 6316 KiB

Open AccessArticle

The Degree of Cardiac Remodelling before Overload Relief Triggers Different Transcriptome and miRome Signatures during Reverse Remodelling (RR)—Molecular Signature Differ with the Extent of RR

by Patrícia G. Rodrigues, Daniela Miranda-Silva, Xidan Li, Cláudia Sousa-Mendes, Ricardo Martins-Ferreira, Zaher Elbeck, Adelino F. Leite-Moreira, Ralph Knöll and Inês Falcão-Pires

Int. J. Mol. Sci. 2020, 21(24), 9687; https://doi.org/10.3390/ijms21249687 - 18 Dec 2020

Cited by 1 | Viewed by 2409

Abstract

This study aims to provide new insights into transcriptome and miRome modifications occurring in cardiac reverse remodelling (RR) upon left ventricle pressure-overload relief in mice. Pressure-overload was established in seven-week-old C57BL/6J-mice by ascending aortic constriction. A debanding (DEB) surgery was performed seven weeks later in half of the banding group (BA). Two weeks later, cardiac function was evaluated through hemodynamics and echocardiography, and the hearts were collected for histology and small/bulk-RNA-sequencing. Pressure-overload relief was confirmed by the normalization of left-ventricle-end-systolic-pressure. DEB animals were separated into two subgroups according to the extent of cardiac remodelling at seven weeks and RR: DEB1 showed an incomplete RR phenotype confirmed by diastolic dysfunction persistence (E/e’ ≥ 16 ms) and increased myocardial fibrosis. At the same time, DEB2 exhibited normal diastolic function and fibrosis, presenting a phenotype closer to myocardial recovery. Nevertheless, both subgroups showed the persistence of cardiomyocytes hypertrophy. Notably, the DEB1 subgroup presented a more severe diastolic dysfunction at the moment of debanding than the DEB2, suggesting a different degree of cardiac remodelling. Transcriptomic and miRomic data, as well as their integrated analysis, revealed significant downregulation in metabolic and hypertrophic related pathways in DEB1 when compared to DEB2 group, including fatty acid β-oxidation, mitochondria L-carnitine shuttle, and nuclear factor of activated T-cells pathways. Moreover, extracellular matrix remodelling, glycan metabolism and inflammation-related pathways were up-regulated in DEB1. The presence of a more severe diastolic dysfunction at the moment of pressure overload-relief on top of cardiac hypertrophy was associated with an incomplete RR. Our transcriptomic approach suggests that a cardiac inflammation, fibrosis, and metabolic-related gene expression dysregulation underlies diastolic dysfunction persistence after pressure-overload relief, despite left ventricular mass regression, as echocardiographically confirmed. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Graphical abstract

17 pages, 2966 KiB

Open AccessArticle

Elevated Plasma Levels of Circulating Extracellular miR-320a-3p in Patients with Paroxysmal Atrial Fibrillation

by Andrey V. Zhelankin, Sergey V. Vasiliev, Daria A. Stonogina, Konstantin A. Babalyan, Elena I. Sharova, Yurii V. Doludin, Dmitry Y. Shchekochikhin, Eduard V. Generozov and Anna S. Akselrod

Int. J. Mol. Sci. 2020, 21(10), 3485; https://doi.org/10.3390/ijms21103485 - 15 May 2020

Cited by 18 | Viewed by 2905

Abstract

The potential of extracellular circulating microRNAs (miRNAs) as non-invasive biomarkers of atrial fibrillation (AF) has been confirmed by a number of recent studies. However, the current data for some miRNAs are controversial and inconsistent, probably due to pre-analytical and methodological differences. In this work, we attempted to fulfill the basic pre-analytical requirements provided for circulating miRNA studies for application to paroxysmal atrial fibrillation (PAF) research. We used quantitative PCR (qPCR) to determine the relative plasma levels of circulating miRNAs expressed in the heart or associated with atrial remodeling or fibrillation with reported altered plasma/serum levels in AF: miR-146a-5p, miR-150-5p, miR-19a-3p, miR-21-5p, miR-29b-3p, miR-320a-3p, miR-328-3p, miR-375-3p, and miR-409-3p. First, in a cohort of 90 adult outpatient clinic patients, we found that the plasma level of miR-320a-3p was elevated in PAF patients compared to healthy controls and hypertensive patients without AF. We further analyzed the impact of medication therapies on miRNA relative levels and found elevated miR-320a-3p levels in patients receiving angiotensin-converting-enzyme inhibitors (ACEI) therapy. Additionally, we found that miR-320a-3p, miR-21-5p, and miR-146a-5p plasma levels positively correlated with the CHA₂DS₂-Vasc score and were elevated in subjects with CHA₂DS₂-Vasc ≥ 2. Our results indicate that, amongst the analyzed miRNAs, miR-320a-3p may be considered as a potential PAF circulating plasma biomarker, leading to speculation as to whether this miRNA is a marker of platelet state change due to ACEI therapy. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Graphical abstract

17 pages, 3418 KiB

Open AccessArticle

Exploratory Analysis of Circulating miRNA Signatures in Atrial Fibrillation Patients Determining Potential Biomarkers to Support Decision-Making in Anticoagulation and Catheter Ablation

by Naoki Kiyosawa, Kenji Watanabe, Yoshiyuki Morishima, Takeshi Yamashita, Naoharu Yagi, Takuto Arita, Takayuki Otsuka and Shinya Suzuki

Int. J. Mol. Sci. 2020, 21(7), 2444; https://doi.org/10.3390/ijms21072444 - 01 Apr 2020

Cited by 13 | Viewed by 3814

Abstract

Novel biomarkers are desired to improve risk management for patients with atrial fibrillation (AF). We measured 179 plasma miRNAs in 83 AF patients using multiplex qRT-PCR. Plasma levels of eight (i.e., hsa-miR-22-3p, hsa-miR-128-3p, hsa-miR-130a-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-148b-3p, hsa-miR-497-5p, hsa-miR-652-3p) and three (i.e., hsa-miR-144-5p, hsa-miR-192-5p, hsa-miR-194-5p) miRNAs showed positive and negative correlations with CHA₂DS₂-VASc scores, respectively, which also showed negative and positive correlations with catheter ablation (CA) procedure, respectively, within the follow-up observation period up to 6-month after enrollment. These 11 miRNAs were functionally associated with TGF-β signaling and androgen signaling based on pathway enrichment analysis. Seven of possible target genes of these miRNAs, namely TGFBR1, PDGFRA, ZEB1, IGFR1, BCL2, MAPK1 and DICER1 were found to be modulated by more than four miRNAs of the eleven. Of them, TGFBR1, PDGFRA, ZEB1 and BCL2 are reported to exert pro-fibrotic functions, suggesting that dysregulations of these eleven miRNAs may reflect pro-fibrotic condition in the high-risk patients. Although highly speculative, these miRNAs may potentially serve as potential biomarkers, providing mechanistic and quantitative information for pathophysiology in daily clinical practice with AF such as possible pro-fibrotic state in left atrium, which would enhance the risk of stroke and reduce the preference for performing CA. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

Review

Jump to: Research

11 pages, 1223 KiB

Open AccessReview

BET Protein-Mediated Transcriptional Regulation in Heart Failure

by Talha Ijaz and Michael A. Burke

Int. J. Mol. Sci. 2021, 22(11), 6059; https://doi.org/10.3390/ijms22116059 - 04 Jun 2021

Cited by 5 | Viewed by 3487

Abstract

Heart failure is a complex disease process with underlying aberrations in neurohormonal systems that promote dysregulated cellular signaling and gene transcription. Over the past 10 years, the advent of small-molecule inhibitors that target transcriptional machinery has demonstrated the importance of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in regulating gene transcription in multiple mouse models of cardiomyopathy. BETs bind to acetylated histone tails and transcription factors to integrate disparate stress signaling networks into a defined gene expression program. Under myocardial stress, BRD4, a BET family member, is recruited to superenhancers and promoter regions of inflammatory and profibrotic genes to promote transcription elongation. Whole-transcriptome analysis of BET-dependent gene networks suggests a major role of nuclear-factor kappa b and transforming growth factor-beta in the development of cardiac fibrosis and systolic dysfunction. Recent investigations also suggest a prominent role of BRD4 in maintaining cardiomyocyte mitochondrial respiration under basal conditions. In this review, we summarize the data from preclinical heart failure studies that explore the role of BET-regulated transcriptional mechanisms and delve into landmark studies that define BET bromodomain-independent processes involved in cardiac homeostasis. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

20 pages, 641 KiB

Open AccessReview

Non-Coding RNAs as Blood-Based Biomarkers in Cardiovascular Disease

by Raquel Figuinha Videira, Paula A. da Costa Martins and Inês Falcão-Pires

Int. J. Mol. Sci. 2020, 21(23), 9285; https://doi.org/10.3390/ijms21239285 - 05 Dec 2020

Cited by 12 | Viewed by 2438

Abstract

In 2020, cardiovascular diseases (CVDs) remain a leading cause of mortality and morbidity, contributing to the burden of the already overloaded health system. Late or incorrect diagnosis of patients with CVDs compromises treatment efficiency and patient’s outcome. Diagnosis of CVDs could be facilitated by detection of blood-based biomarkers that reliably reflect the current condition of the heart. In the last decade, non-coding RNAs (ncRNAs) present on human biofluids including serum, plasma, and blood have been reported as potential biomarkers for CVDs. This paper reviews recent studies that focus on the use of ncRNAs as biomarkers of CVDs. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

9 pages, 636 KiB

Open AccessReview

Epigenetics and Heart Failure

by Syeda Shegufta Ameer, Mohammad Bakhtiar Hossain and Ralph Knöll

Int. J. Mol. Sci. 2020, 21(23), 9010; https://doi.org/10.3390/ijms21239010 - 27 Nov 2020

Cited by 10 | Viewed by 3110

Abstract

Epigenetics refers to changes in phenotypes without changes in genotypes. These changes take place in a number of ways, including via genomic DNA methylation, DNA interacting proteins, and microRNAs. The epigenome is the second dimension of the genome and it contains key information that is specific to every type of cell. Epigenetics is essential for many fundamental processes in biology, but its importance in the development and progression of heart failure, which is one of the major causes of morbidity and mortality worldwide, remains unclear. Our understanding of the underlying molecular mechanisms is incomplete. While epigenetics is one of the most innovative research areas in modern biology and medicine, compounds that directly target the epigenome, such as epidrugs, have not been well translated into therapies. This paper focuses on epigenetics in terms of genomic DNA methylation, such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications. These appear to be more dynamic than previously anticipated and may underlie a wide variety of conditions, including heart failure. We also outline possible new strategies for the development of novel therapies. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

30 pages, 1633 KiB

Open AccessReview

Genetics and Epigenetics of Atrial Fibrillation

by Estefanía Lozano-Velasco, Diego Franco, Amelia Aranega and Houria Daimi

Int. J. Mol. Sci. 2020, 21(16), 5717; https://doi.org/10.3390/ijms21165717 - 10 Aug 2020

Cited by 45 | Viewed by 5509

Abstract

Atrial fibrillation (AF) is known to be the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence exponentially increases with age and could reach up to 8% in the elderly population. The management of AF is a complex issue that is addressed by extensive ongoing basic and clinical research. AF centers around different types of disturbances, including ion channel dysfunction, Ca²⁺-handling abnormalities, and structural remodeling. Genome-wide association studies (GWAS) have uncovered over 100 genetic loci associated with AF. Most of these loci point to ion channels, distinct cardiac-enriched transcription factors, as well as to other regulatory genes. Recently, the discovery of post-transcriptional regulatory mechanisms, involving non-coding RNAs (especially microRNAs), DNA methylation, and histone modification, has allowed to decipher how a normal heart develops and which modifications are involved in reshaping the processes leading to arrhythmias. This review aims to provide a current state of the field regarding the identification and functional characterization of AF-related epigenetic regulatory networks Full article

(This article belongs to the Special Issue Epigenetic Mechanisms of Cardiac Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Epigenetic Mechanisms of Cardiac Disease

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI