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Noncoding RNA regulation. Different mechanisms of action of noncoding RNAs in epigenetic regulations. (1) <50 nt: MicroRNAs (miRNAs): miRNAs complement mRNAs and promote mRNA silencing or degradation. Small interfering RNAs(siRNA): silences gene expression. (2) 50-500 nt: nucleolar small RNA(snoRNA): snoRNA biological function was initially found to modify rRNA. Nuclear small RNA(snRNA): snRNA function is to combine with protein factors to form small nuclear ribonucleoprotein particle and perform the function of splicing mRNA. Transport RNA (tRNA): the main function is to carry amino acids into the ribosome and synthetic proteins with the guidance of mRNA. Ribosomal RNA (rRNA): it binds to proteins to form ribosomes.Its function is to act as a scaffold for mRNA, enabling mRNA molecules to unfold on it to achieve protein synthesis. (3) >500 nt: long noncoding RNAs (lncRNAs): LncRNA acts as mRNA and miRNA endogenous sponges regulating gene expression. Circular RNAs (cirRNAs): circRNA molecules are rich in miRNA-binding sites and act as miRNA sponges in cells, thereby lifting the inhibition of miRNA on target genes and increasing the expression level of target genes. This figure was created with the aid of Biorender (https://biorender.com/)
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Epigenetics is closely related to cardiovascular diseases. Genome-wide linkage and association analyses and candidate gene approaches illustrate the multigenic complexity of cardiovascular disease. Several epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding RNA, which are of importance for cardiovascular disease deve...
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... ribosomal RNAs, transport RNAs, small nuclear RNAs, small nucleolar RNAs, microRNAs (miRNAs), mRNA, and other known functions, as well as those with unknown functions. These RNAs have common feature that they can be transcribed from the genome but not translated into proteins, performing their respective biological functions at the RNA level (Fig. 3). Noncoding RNAs can be divided into three categories according to length: <50 nt: miRNA, small interfering RNAs, etc. 50-500 nt: ribosomal RNA, transport RNA, nuclear small RNA, nucleolar small RNA, etc. >500 nt: long mRNA-like ncRNAs, long noncoding RNAs (lncRNAs) without polyadenylate tails, ...
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Cancer cells display pervasive changes in DNA methylation, disrupted patterns of histone posttranslational modification, chromatin composition or organization and regulatory element activities that alter normal programs of gene expression. It is becoming increasingly clear that disturbances in the epigenome are hallmarks of cancer, which are target...
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... Its role in physiological and pathological conditions has sparked a keen interest in personalized medicine (15). Research in the cardiovascular field indicates that the three major epigenetic modifications-DNA methylation, histone modification, and non-coding RNA modification-may play a crucial role in the occurrence and development of cardiovascular diseases (16). Recent studies suggest a correlation between epigenetics and the pathogenesis of cardiovascular diseases and AAA (17)(18)(19), including the role of DNA methyltransferases, the modification of histones, the mechanisms of non-coding RNA and RNA modification, which will be described in detail below. ...
... Furthermore, histone modifications, particularly histone methylation and acetylation, which have been extensively studied, play a regulatory role in cardiovascular diseases, including AAA risk factors such as atherosclerosis and hypertension (16). These study of histone modifications will play some inspiring roles in the study of the mechanism of AAA disease progression. ...
Abdominal Aortic Aneurysm (AAA) is a disease characterized by localized dilation of the abdominal aorta, involving multiple factors in its occurrence and development, ultimately leading to vessel rupture and severe bleeding. AAA has a high mortality rate, and there is a lack of targeted therapeutic drugs. Epigenetic regulation plays a crucial role in AAA, and the treatment of AAA in the epigenetic field may involve a series of related genes and pathways. Abnormal expression of these genes may be a key factor in the occurrence of the disease and could potentially serve as promising therapeutic targets. Understanding the epigenetic regulation of AAA is of significant importance in revealing the mechanisms underlying the disease and identifying new therapeutic targets. This knowledge can contribute to offering AAA patients better clinical treatment options beyond surgery. This review systematically explores various aspects of epigenetic regulation in AAA, including DNA methylation, histone modification, non-coding RNA, and RNA modification. The analysis of the roles of these regulatory mechanisms, along with the identification of relevant genes and pathways associated with AAA, is discussed comprehensively. Additionally, a comprehensive discussion is provided on existing treatment strategies and prospects for epigenetics-based treatments, offering insights for future clinical interventions.
... Because of that, the use of DNA methylation inhibitors for the treatment of cardiac fibrosis is still in preclinical stages, despite their promising potential. Further studies investigating DNA methylation will enable the application of targeted epigenetic therapies to the clinic for diagnosing and treating cardiac fibrosis [74]. ...
Cardiac fibrosis, a process characterized by excessive extracellular matrix (ECM) deposition, is a common pathological consequence of many cardiovascular diseases (CVDs) normally resulting in organ failure and death. Cardiac fibroblasts (CFs) play an essential role in deleterious cardiac remodeling and dysfunction. In response to injury, quiescent CFs become activated and adopt a collagen-secreting phenotype highly contributing to cardiac fibrosis. In recent years, studies have been focused on the exploration of molecular and cellular mechanisms implicated in the activation process of CFs, which allow the development of novel therapeutic approaches for the treatment of cardiac fibrosis. Transcriptomic analyses using single-cell RNA sequencing (RNA-seq) have helped to elucidate the high cellular diversity and complex intercellular communication networks that CFs establish in the mammalian heart. Furthermore, a significant body of work supports the critical role of epigenetic regulation on the expression of genes involved in the pathogenesis of cardiac fibrosis. The study of epigenetic mechanisms, including DNA methylation, histone modification, and chromatin remodeling, has provided more insights into CF activation and fibrotic processes. Targeting epigenetic regulators, especially DNA methyltransferases (DNMT), histone acetylases (HAT), or histone deacetylases (HDAC), has emerged as a promising approach for the development of novel anti-fibrotic therapies. This review focuses on recent transcriptomic advances regarding CF diversity and molecular and epigenetic mechanisms that modulate the activation process of CFs and their possible clinical applications for the treatment of cardiac fibrosis.
... ∆B-lines have been included in a weighted score exercise-induced along with NT-proBNP, systolic pulmonary artery pressure and two indices derived from CPET (peak oxygen consumption [VO 2 ] and ventilation [VE]/carbon dioxide production [VCO 2 ] slope). The score improves the prognostic stratification of patients with cardiovascular risk at the risk of transition to overt HF, and those with a definite diagnosis of HF characterised by a poor outcome [44]. ...
... Epigenetic changes might be divided into three major clusters: (i) DNA methylation, (ii) post-translational modifications of histone proteins, (iii) and noncoding RNA regulation [44]. ...
Cardiometabolic diseases (CMDs) are interrelated and multifactorial conditions, including arterial hypertension, type 2 diabetes, heart failure, coronary artery disease, and stroke. Due to the burden of cardiovascular morbidity and mortality associated with CMDs’ increasing prevalence, there is a critical need for novel diagnostic and therapeutic strategies in their management. In clinical practice, innovative methods such as epicardial adipose tissue evaluation, ventricular–arterial coupling, and exercise tolerance studies could help to elucidate the multifaceted mechanisms associated with CMDs. Similarly, epigenetic changes involving noncoding RNAs, chromatin modulation, and cellular senescence could represent both novel biomarkers and targets for CMDs. Despite the promising data available, significant challenges remain in translating basic research findings into clinical practice, highlighting the need for further investigation into the complex pathophysiology underlying CMDs.
... In recent years, due to the continuous acceleration of population aging and urbanization, the people suffering cardiovascular diseases (CVDs) worldwide boost rapidly, which have become the primary cause of death all over the world (Shi et al., 2022). Among CVDs, end-stage severe obstructive ones such as coronary heart disease and severe lower limb ischemia, are very risky, but their preferred treatment, the vascular transplantation, is largely restricted by lacking enough available small diameter vascular grafts (SDVGs, inner diameter≤6 mm) (Wei et al., 2022). ...
... Compared with pure PCL transplantation, dipeptide modified transplantation showed good patency and tissue regeneration at 4 weeks after implantation, as indicated by stem cell recruitment, rapid endothelialization and formation of functional SMC layer. ES PCL grafts were functionalized by immobilizing biotin/avidin coupled stem cell antigen-1 (SCA-1) antibody, which was proved to specifically recruit SCA-1 positive SMPCs under static and dynamic flow culture ( Figure 4) (Wang H. et al., 2022) In a rat abdominal aorta replacement model, the grafts initiated rapid re-endothelialization and smooth muscle regeneration by actively recruiting and capturing SMPCs from resident tissues and circulation, finally forming new tissues that were very structurally similar to natural arterial tissues. In another study, Yu et al. coated heparin on ES SDVGs and then stably grafted SDF-1α on heparin (Yu et al., 2012). ...
... The intrinsic problems for ESCs are the ethical problems for obtaining them by destroying early embryos and their Application of unipotent stem cells (SMPCs herein) in ES/SC SDVGs. Reprinted with permission from reference (Wang H. et al., 2022). Copyright 2022, E.lsevier. ...
The exploration of the next-generation small diameter vascular grafts (SDVGs) will never stop until they possess high biocompatibility and patency comparable to autologous native blood vessels. Integrating biocompatible electrospinning (ES) matrices with highly bioactive stem cells (SCs) provides a rational and promising solution. ES is a simple, fast, flexible and universal technology to prepare extracellular matrix-like fibrous scaffolds in large scale, while SCs are valuable, multifunctional and favorable seed cells with special characteristics for the emerging field of cell therapy and regenerative medicine. Both ES matrices and SCs are advanced resources with medical application prospects, and the combination may share their advantages to drive the overcoming of the long-lasting hurdles in SDVG field. In this review, the advances on SDVGs based on ES matrices and SCs (including pluripotent SCs, multipotent SCs, and unipotent SCs) are sorted out, and current challenges and future prospects are discussed.
... There are few clinical reports on cardiotoxicity of epigenetic drugs, suggesting the promising potential of epigenetic drugs in counteracting anticancer drug-induced cardiotoxicity. Moreover, more clinical trials are needed to confirm the effectiveness and safety of epigenetic drugs in treating anticancer drug-induced cardiotoxicity [89]. ...
Cardiovascular disease is the main factor contributing to the global burden of diseases, and the cardiotoxicity caused by anticancer drugs is an essential component that cannot be ignored. With the development of anticancer drugs, the survival period of cancer patients is prolonged; however, the cardiotoxicity caused by anticancer drugs is becoming increasingly prominent. Currently, cardiovascular disease has emerged as the second leading cause of mortality among long-term cancer survivors. Anticancer drug-induced cardiotoxicity has become a frontier and hot topic. The discovery of epigenetics has given the possibility of environmental changes in gene expression, protein synthesis, and traits. It has been found that epigenetics plays a pivotal role in promoting cardiovascular diseases, such as heart failure, coronary heart disease, and hypertension. In recent years, increasing studies have underscored the crucial roles played by epigenetics in anticancer drug-induced cardiotoxicity. Here, we provide a comprehensive overview of the role and mechanisms of epigenetics in anticancer drug-induced cardiotoxicity.
... The DNMT family is divided into five categories: 1, 2, 3A, 3B, and 3L [28]. Studies have confirmed that the UHRF protein family, zinc finger protein family, and methyl CPG binding domain family can recognize DNA methylation and bind methyl groups [148] DNA demethylases help modify methyl groups and remove methylation. Although no definitive DNA demethylases have been identified, studies have shown that demethylation is achieved by TET enzymes [149]. ...
The field of transcriptional regulation has revealed the vital role of chromatin modifiers in human diseases from the beginning of functional exploration to the process of participating in many types of disease regulatory mechanisms. Chromatin modifiers are a class of enzymes that can catalyze the chemical conversion of pyrimidine residues or amino acid residues, including histone modifiers, DNA methyltransferases, and chromatin remodeling complexes. Chromatin modifiers assist in the formation of transcriptional regulatory circuits between transcription factors, enhancers, and promoters by regulating chromatin accessibility and the ability of transcription factors to acquire DNA. This is achieved by recruiting associated proteins and RNA polymerases. They modify the physical contact between cis-regulatory factor elements, transcription factors, and chromatin DNA to influence transcriptional regulatory processes. Then, abnormal chromatin perturbations can impair the homeostasis of organs, tissues, and cells, leading to diseases. The review offers a comprehensive elucidation on the function and regulatory mechanism of chromatin modifiers, thereby highlighting their indispensability in the development of diseases. Furthermore, this underscores the potential of chromatin modifiers as biomarkers, which may enable early disease diagnosis. With the aid of this paper, a deeper understanding of the role of chromatin modifiers in the pathogenesis of diseases can be gained, which could help in devising effective diagnostic and therapeutic interventions.
... The regulatory control mechanisms of high BP and kidney diseases, governed by intricate molecular and pathophysiological systems, indicate that genetic determinants and epigenetic factors govern gene regulation, expression, and function, which greatly influence preconditional settings and susceptibility to the development of hypertension and kidney injury and dysfunction. [7][8][9][10] BP is the result of cardiac output and vascular peripheral resistance, which are influenced by many physiological, neuroendocrine, and humoral functions. The pathogenesis of hypertension varies between individuals, although elevated vascular resistance is common to most cases 11,12 ; however, the molecular mechanisms of genetic and epigenetic regulation of BP are not well understood. ...
... 11,85,86 Epigenome-wide investigations of high BP have suggested that epigenetic changes associated with DNA methylation and histone modifications activate gene expression regulation, and function, initiating the onset and progression of hypertension, kidney injury, and cardiovascular dysfunction. 10,87,88 Experimental approaches targeting key epigenetic enzymes, namely DNMTs (DNA methyl transferases), HATs (histone acetylases), HDACs (histone deacetylases), and HMTs (histone methyl transferases), could provide new tools for the diagnosis, treatment, and prevention of hypertension. The kidney is a rich source of acetylated lysine, a critical element of epigenetic programming, including BP. 89 The genetic sequence is usually identical in every cell of an individual organism and remains constant though the lifespan, while epigenomic mediators may vary between cell types. ...
The pioneering work of Dr Lewis K. Dahl established a relationship between kidney, salt, and high blood pressure (BP), which led to the major genetic-based experimental model of hypertension. BP, a heritable quantitative trait affected by numerous biological and environmental stimuli, is a major cause of morbidity and mortality worldwide and is considered to be a primary modifiable factor in renal, cardiovascular, and cerebrovascular diseases. Genome-wide association studies have identified monogenic and polygenic variants affecting BP in humans. Single nucleotide polymorphisms identified in genome-wide association studies have quantified the heritability of BP and the effect of genetics on hypertensive phenotype. Changes in the transcriptional program of genes may represent consequential determinants of BP, so understanding the mechanisms of the disease process has become a priority in the field. At the molecular level, the onset of hypertension is associated with reprogramming of gene expression influenced by epigenomics. This review highlights the specific genetic variants, mutations, and epigenetic factors associated with high BP and how these mechanisms affect the regulation of hypertension and kidney dysfunction.
... Epigenetic modifications have also been associated with cardiovascular diseases such as coronary heart disease, acute myocardial infarction, heart failure, vascular calcification, and hypertension [65]. Aberrant DNA methylation patterns, histone modifications, and noncoding RNA regulation were shown to impact the function of cardiovascular disease-related genes and their expression levels, thus affecting cardiovascular disease progression. ...
The epigenetic revolution has led to a paradigm shift in our understanding of gene regulation and function. Epigenetic modifications, including DNA methylation, post-translational histone modifications, and regulatory noncoding RNAs, display unique features, such as reversibility and transgenerational inheritance. A great variety of environmental and lifestyle factors can cause changes in the epigenome. Epigenetic alterations can contribute to the underlying mechanisms of human diseases including cancer, cardiovascular, neurological, psychiatric, autoimmune, metabolic and inherited. The chapter focuses on the fine interplay between environmental stress, the epigenetic adaptive responses, and how the inability to adapt may trigger disease outcomes. A model of the epigenetic disease is postulated, epigenetic disease adapta-tional model (EDAM), according to which the epigenetic disease develops as a failure to adapt to environmental stressors. This may occur in at least two possible scenarios: (1) when the epigenetic adaptational programs are not adequate to stress nature, duration, intensity and/or stage of action and (2) when the epigenetic adaptational programs are not adequate to the situation. In the second scenario, the stressful situation is wrongly considered the most feasible situation, and the stressful conditions are taken as "norm." The proposed model highlights important topics for future research in the field of epigenetics and disease.
... DNA methylation can act as a regulatory switch for gene expression, with methylated CpG sites often associated with gene repression or silencing. The methylation status of various genes is widely recognized for significant involvement in development of cardiovascular disease alongside a clear potential to serve as a pathological diagnostic biomarker (108). Additionally, it is wellestablished that disparities in DNA methylation between sexes influence gene expression by means of epigenetic mechanisms (109). ...
Cardiac sex differences represent a pertinent focus in pursuit of the long-awaited goal of personalized medicine. Despite evident disparities in the onset and progression of cardiac pathology between sexes, historical oversight has led to the neglect of gender-specific considerations in the treatment of patients. This oversight is attributed to a predominant focus on male samples and a lack of sex-based segregation in patient studies. Recognizing these sex differences is not only relevant to the treatment of cisgender individuals; it also holds paramount importance in addressing the healthcare needs of transgender patients, a demographic that is increasingly prominent in contemporary society. In response to these challenges, various agencies, including the National Institutes of Health, have actively directed their efforts toward advancing our comprehension of this phenomenon. Epigenetics has proven to play a crucial role in understanding sex differences in both healthy and disease states within the heart. This review presents a comprehensive overview of the physiological distinctions between males and females during the development of various cardiac pathologies, specifically focusing on unraveling the genetic and epigenetic mechanisms at play. Current findings related to distinct sex-chromosome compositions, the emergence of gender-biased genetic variations, and variations in hormonal profiles between sexes are highlighted. Additionally, the roles of DNA methylation, histone marks, and chromatin structure in mediating pathological sex differences are explored. To inspire further investigation into this crucial subject, we have conducted global analyses of various epigenetic features, leveraging data previously generated by the ENCODE project.
... These well-conserved ()modifications trigger high order heterochromatin packaging that form nucleation sites for recruiting DNAbinding proteins and RNA molecules. Histone methylation plays a major role in the pathogenesis of diabetes 8 and cardiovascular diseases 9 where many factors affect the levels of histone methyltransferases 10 , most importantly the coupling of histone methylation and DNA methylation 11 in neurodevelopmental disorders 12,13 . ...
The establishment and maintenance of heterochromatin, a specific chromatin structure essential for genomic stability and regulation, rely on intricate interactions between chromatin-modifying enzymes and nucleosomal histone proteins. However, the precise trigger for these modifications remains unclear, thus highlighting the need for a deeper understanding of how methyltransferases facilitate histone methylation among others. Here, we investigate the molecular mechanisms underlying heterochromatin assembly by studying the interaction between the H3K9 methyltransferase Clr4 and H3K9-methylated nucleosomes. Using a combination of liquid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy, we elucidate the structural basis of Clr4 binding to H3K9-methylated nucleosomes. Our results reveal that Clr4 engages with nucleosomes through its chromodomain and disordered regions to promote de novo methylation. This study provides crucial insights into the molecular mechanisms governing heterochromatin formation by highlighting the significance of chromatin-modifying enzymes in genome regulation and disease pathology.
