The benefits of cardiac rehabilitation (CR) have been demonstrated in patients after myocardial infarction (MI), and in patients with chronic heart failure (HF). The core components of the CR program include improvement in exercise tolerance and optimization of coronary risk factors (i.e., lipid and lipoprotein profiles, body weight, blood glucose levels, blood pressure levels, and smoking cessation). Indeed, CR has been shown to improve exercise capacity, control of cardiovascular risk factors, quality of life, hospital readmission, and mortality rates. Nonetheless, pre- and clinical CR and exercise training models are an enormous source of potential beneficial mechanisms that can be exploited for cardiac disease therapy. Consequently, in this review, we aim to explore the unique benefits of CR in HF and coronary artery disease, focusing on the epigenetic mechanisms involved and their translational relevance. These mechanisms may represent novel therapeutic targets to promote functional recovery after cardiac injury, and non-coding RNAs could be predictive biomarkers for CR success in patients.

TGF-β1 has been reported to suppress miR-130a expression, while being elevated in patients with type 2 diabetes mellitus (T2DM). And IL-18, a potential target of miR-130a, is also up-regulated in T2DM patients. In this study, we aim to investigate the potential involvement of the TGFβ1/miR-130a/IL-18 axis underlying the dysfunction of endothelial progenitor cells (EPCs) in T2DM patients. We performed luciferase assays to confirm the molecular binding between miR-130a, TGF-β1 and IL-18, and real-time PCR and ELISA were performed to observe the changes of TGF-β1, miR-130a, IL-18 and IFN-γ in different cell groups. Tube formation assay, cell adhesion assay and Transwell assay were performed to evaluate effect of TGF-β1/miR-130a/IL-18 axis on the EPCs functions. Accordingly, in EPCs treated with TGF-β1, we found that the levels of miR-130a were reduced, and its expressions were also negatively correlated with the expressions of IL-18 in the EPC groups. Luciferase assays validated IL-18 as a target gene of miR-130a. The over-expression of IL-18, as well as the knockdown of miR-130a, not only increased the expressions of TGF-β1 in EPCs, but also promoted the tube formation, adhesion and migration of EPCs. By contrast, the knockdown of IL-18, as well as the over-regulation of miR-130a, exhibited suppressive effect on the levels of TGF-β1, while inhibiting the tube formation, adhesion and migration of EPCs. In this study, we elucidated the impact of the TGFβ1/miR-130a/IL-18 signaling pathway on the function of EPCs, thus providing theoretical basis for the development of miRNA-targeted therapeutic strategies for patients withT2DM and associated complications.

MicroRNAs (miRNAs) add a new dimension to HD forecast, diagnosis, and therapy based on the potential applications. The miRNA-related research in the heart disease (HD) field has received close attention in the past two decades. However, there is a lack of studies that comprehensively and objectively analyze the current situation of miRNA application in the HD field using the bibliometrics method.

To comprehensively analyze the global scientific outputs of miRNAs in HD research from 2004 to 2023.

All the articles and reviews of miRNA-related research in the HD field were retrieved using the Web of Science core collection (WOSCC) title search, and bibliometric analysis was performed in Microsoft Excel 2019, CiteSpace, VOSviewer, and Bibliometrics (R-Tool of R-Studio).

3,874 publications were included in the bibliometric analysis. Collaborative network analysis indicates that China with the maximum number of publications (2,063) and the USA with the highest total citations (59,331) are influential countries in this field. Peking Union Medical College is the most prolific university with the maximum publications (134), and the University of California System is the most authoritative institution regarding betweenness centrality (0.27). PLOS ONE tops the journal list of publications, closely followed by the International Journal of Molecular Sciences and Scientific Reports with more than 100 articles. Considering the number of publications, citations, and total link strength overall, Olson. Eric N, Van Rooij Eva, Thum Thomas, Yang Baofeng, Wang Kun; and Lu Yanjie are authoritative authors in this field. The expression changes and regulatory mechanisms of specific miRNAs in various heart biological and pathophysiological processes have been the continuous research hotspots. "exosomes", "extracellular vesicles", "autophagy", and "management" have been novel hot research topics since 2018, which focused on the diagnosis and treatment of HD. The current research development trend is how to translate the achievement of miRNA-related diagnosis and therapeutic drugs for HD into the clinic.

Our study revealed the intellectual structure of miRNA in HD research, which may help scholars understand this field comprehensively and find partners.

The 2024 Nobel Prize in Physiology or Medicine has been awarded to two pioneering researchers, Victor Ambros and Gary Ruvkun, marking the fourth time research using Caenorhabditis elegans (C. elegans) has received this prestigious recognition. With a rapid life cycle of just 3.5 days and four distinct larval stages, C. elegans serves as an ideal model for exploring complex genetic mechanisms, particularly heterochronic gene regulation. Ambros and Ruvkun's groundbreaking work on lin-4 and lin-14 genes in C. elegans revealed that lin-4 functions as a 22-nucleotide small RNA-now known as a microRNA (miRNA)-that binds complementarily to the 3' UTR of lin-14 mRNA, effectively inhibiting LIN-14 protein synthesis. This discovery was the first demonstration of miRNA in post-transcriptional gene regulation, a finding that has since reshaped our understanding of genetic regulation across species. Their research on small RNAs in C. elegans not only opened a new paradigm in molecular biology but also highlighted the power of this model organism in uncovering universal biological principles.

Males and females exhibit distinct anatomic and functional characteristics of the heart, predisposing them to specific disease states.

We identified microRNAs (miRNAs/miR) with sex-differential expression in mouse hearts.

Four conserved miRNAs are present in a single locus on the X-chromosome and are expressed at higher levels in females than males. We show miRNA, miR-871, is responsible for decreased expression of the protein SRL (sarcalumenin) in females. SRL is involved in calcium signaling, and we show it contributes to differences in electrophysiology between males and females. miR-871 overexpression mimics the effects of the cardiac physiology of conditional cardiomyocyte-specific Srl-null mice. Inhibiting miR-871 with an antagomir in females shortened ventricular repolarization. The human orthologue of miR-871, miR-888, coevolved with the SRL 3' untranslated region and regulates human SRL.

These data highlight the importance of sex-differential miRNA mechanisms in mediating sex-specific functions and their potential relevance to human cardiac diseases.

Cardiovascular diseases (CVDs) are a leading cause of death worldwide, and new therapeutic strategies are urgently needed. In recent years, enhancer RNAs (eRNAs) have gradually attracted attention because they offer new directions for the treatment of CVDs. Super-enhancer RNAs (seRNAs) are a subset of non-coding RNAs that are transcribed from regions of the genome known as super enhancers, which are large clusters of enhancers with a high density of transcription factors and cofactors. These regions play a pivotal role in regulating genes involved in cell identity and disease progression. This article reviews the characteristics of seRNAs, their expression patterns, and regulatory mechanisms in the cardiovascular system. We also explore their role in the occurrence and development of CVDs, as well as their potential as diagnostic biomarkers and therapeutic targets. Currently, therapies targeting seRNAs are a research hotspot. The development of specific inhibitors or activators is expected to facilitate precise interventions for CVDs. In addition, the use of gene editing techniques to modify relevant eRNA introduces new possibilities for disease treatment. This review aims to provide a comprehensive overview of seRNAs in CVDs and discusses their potential as a novel class of therapeutic targets.

Cardiac remodelling involves structural, cellular and molecular alterations in the heart after injury, resulting in progressive loss of heart function and ultimately leading to heart failure. Circular RNAs (circRNAs) are a recently rediscovered class of non-coding RNAs that play regulatory roles in the pathogenesis of cardiovascular diseases, including heart failure. Thus, a more comprehensive understanding of the role of circRNAs in the processes governing cardiac remodelling may set the ground for the development of circRNA-based diagnostic and therapeutic strategies. In this review, the current knowledge about circRNA origin, conservation, characteristics and function is summarized. Bioinformatics and wet-lab methods used in circRNA research are discussed. The regulatory function of circRNAs in cardiac remodelling mechanisms such as cell death, cardiomyocyte hypertrophy, inflammation, fibrosis and metabolism is highlighted. Finally, key challenges and opportunities in circRNA research are discussed, and orientations for future work to address the pharmacological potential of circRNAs in heart failure are proposed. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder associated with an increased risk of arrhythmias, heart failure, and sudden cardiac death. Current imaging and clinical markers are not fully sufficient in accurate diagnosis and patient risk stratification. Although known cardiac biomarkers in blood are used, they lack specificity for HCM and primarily stratify for death due to heart failure in overt cases. Non-coding RNAs, particularly microRNAs, have emerged as promising biomarkers due to their role in regulating gene expression in both healthy and pathological hearts. Circulating microRNA signatures may dynamically reflect the progression of HCM, offering potential utility in diagnosis and disease monitoring as well as inform biologic pathways for innovative therapeutic strategies. However, studying microRNAs in cardiovascular diseases is still in its early stages and poses many challenges. This review focuses on emerging research perspectives using advanced cardiac magnetic resonance techniques. We presume, that the search for circulating miR signatures associated with specific adverse myocardial features observed on cardiac magnetic resonance imaging - such as fibrosis, disarray, and microvascular disease - represents a promising direction in HCM research.

Heart failure (HF) has a multifaceted and complex pathophysiology. Beyond neurohormonal, renin-angiotensin-aldosterone system, and adrenergic hyperactivation, a role for other pathophysiological determinants is emerging. Genetic and epigenetic factors are involved in this syndrome. In many maladaptive processes, the role of microRNAs (miRNAs) has been recently demonstrated. MiRNAs are small endogenous non-coding molecules of RNA involved in gene expression regulation, and they play a pivotal role in intercellular communication, being involved in different biological and pathophysiological processes. MiRNAs can modulate infarct area size, cardiomyocytes restoration, collagen deposition, and macrophage polarization. MiRNAs may be considered as specific biomarkers of hypertrophy and fibrosis. MiRNAs have been proposed as a therapeutical tool because their administration can contrast with myocardial pathophysiological remodeling leading to HF. Antimir and miRNA mimics are small oligonucleotides which may be administered in several manners and may be able to regulate the expression of specific and circulating miRNAs. Studies on animal models and on healthy humans demonstrate that these molecules are well tolerated and effective, opening the possibility of a therapeutic use of miRNAs in cases of HF. The application of miRNAs for diagnosis, prognostic stratification, and therapy fits in with the new concept of a personalized and tailored approach to HF.

Cardiovascular disease (CVD) is a major global health concern. The number of people with CVD is expected to rise due to aging populations and increasing risk factors such as obesity and diabetes. Identifying new molecular markers is crucial for early diagnosis and treatment. Among these, plasma levels of some miRNAs, specifically expressed in cardiac and skeletal muscle, known as myomiRs, have gained attention for their roles in cardiovascular health. This study analyzed the plasma levels of miR-133a-3p, -133b, and -206 in the pathogenesis of cardiovascular diseases. Using a case-control study design with patients recruited from several nursing homes from Calabria (southern Italy) characterized by different types of CVD compared with non-CVD controls, we found downregulation of miR-133a-3p in heart failure and miR-133b in stroke, along with the overall decreased expression of miR-133b and miR-206 in CVD patients, although they showed low specificity as biomarkers of CVD (as based on ROC analysis). In silico functional characterization of their targets and signaling pathways revealed their involvement in critical cardiovascular processes. Although further research is necessary to fully elucidate their mechanisms and clinical utility, the findings reported here may provide insight into the potential contribution of myomiRs in the cardiovascular injury framework, also offering indications for new research directions.

Dysfunctions in miRNA production have been recently investigated as predictors of neoplasms and their therapeutic strategies. In this review, we summarize the available knowledge on miRNAs and cardiac tumors (such as myxoma) and mediastinal tumors (such as thymoma) and propose new avenues for future research. MiRNAs are crucial for cardiac development through the expression of cardiac transcription factors (miR-335-5p), hinder the cell cycle by modulating the activity of transcription factors (miR-126-3p, miR-320a), modulate the production of inflammatory factors such as interleukins (miR-217), and interfere with cell proliferation or apoptosis (miR-218, miR-634 and miR-122). Current and future research on miRNAs is essential, as a deep understanding could lead to a revolution in the field of diagnostics and prevention of neoplastic diseases.

The potential of the pericardial space as a therapeutic delivery tool for cardiac fibrosis and heart failure (HF) treatment has yet to be elucidated. Recently, miRNAs and exosomes have been discovered to be present in human pericardial fluid (PF). Novel studies have shown characteristic human PF miRNA compositions associated with cardiac diseases and higher miRNA expressions in PF compared to peripheral blood. Five key studies found differentially expressed miRNAs in HF, angina pectoris, aortic stenosis, ventricular tachycardia, and congenital heart diseases with either atrial fibrillation or sinus rhythm. As miRNA-based therapeutics for cardiac fibrosis and HF showed promising results in several in vivo studies for multiple miRNAs, we hypothesize a potential role of miRNA-based therapeutics delivered through the pericardial cavity. This is underlined by the favorable results of the first phase 1b clinical trial in this emerging field. Presenting the first human miRNA antisense drug trial, inhibition of miR-132 by intravenous administration of a novel antisense oligonucleotide, CDR132L, established efficacy in reducing miR-132 in plasma samples in a dose-dependent manner. We screened the literature, provided an overview of the miRNAs and exosomes present in PF, and drew a connection to those miRNAs previously elucidated in cardiac fibrosis and HF. Further, we speculate about clinical implications and potential delivery methods.

microRNAs (miRNAs) are small regulatory RNAs implicated in various cardiac disorders. In this review, the role of miRNAs is discussed in relation to acute myocardial infarction and chronic heart failure. In both settings, miRNAs are altered, contributing to injury and adverse remodeling. Notably, miRNA profiles differ between acute ischemic injury and progressive heart failure. Owing to miRNA variabilities between disease stages and delivery difficulties, translation of animal studies to the clinic remains challenging. The identification of distinct miRNA signatures could lead to the development of miRNA therapies tailored to different disease stages. Here, we summarize the current understanding of miRNAs in acute and chronic cardiac diseases, identify knowledge gaps and discuss progress in developing miRNA-based treatment strategies.

Argonaute (AGO), a component of RNA-induced silencing complexes (RISCs), is a representative RNA-binding protein (RBP) known to bind with mature microRNAs (miRNAs) and is directly involved in post-transcriptional gene silencing. However, despite the biological significance of miRNAs, the roles of other miRNA-binding proteins (miRBPs) remain unclear in the regulation of miRNA loading, dissociation from RISCs and extracellular release. In this study, we performed protein arrays to profile miRBPs and identify 118 RBPs that directly bind to miRNAs. Among those proteins, the RBP quaking (QKI) inhibits extracellular release of the mature microRNA let-7b by controlling the loading of let-7b into extracellular vesicles via additional miRBPs such as AUF1 (also known as hnRNPD) and hnRNPK. The enhanced extracellular release of let-7b after QKI depletion activates Toll-like receptor 7 (TLR7) and promotes the production of proinflammatory cytokines in recipient cells, leading to brain inflammation in the mouse cortex. Thus, this study reveals the contribution of QKI to the inhibition of brain inflammation via regulation of extracellular let-7b release.

Receptors for activated C kinases (RACKs) have been shown to coordinate PKC-mediated hypertrophic signalling in mice. However, little information is available on its participation in embryonic gene expression. This study investigated the involvement of RACK1 in the expression of embryonic genes in a zebrafish (ZF) ex vivo heart culture model by using phenylephrine (PE) or a growth factors cocktail (GFs) as a prohypertrophic/regeneration stimulus. Blebbistatin (BL) inhibition has also been studied for its ability to block the signal transduction actions of some PEs. qRT‒PCR and immunoblot analyses confirmed the upregulation of RACK1 in the PE- and GFs-treated groups. BL administration counteracted PE-induced hypertrophy and downregulated RACK1 expression. Immunohistochemical analyses of the heart revealed the colocalization of RACK1 and embryonic genes, namely, Gata4, Wt1, and Nfat2, under stimulation, whereas these genes were expressed at lower levels in the BL treatment group. Culturing ZF heart cells activated via GFs treatment increased the expression of RACK1. The overexpression of RACK1 induced by the transfection of recombinant RACK1 cDNA in ZF heart cells increased the expression of embryonic genes, especially after one week of GFs treatment. In summary, these results support the involvement of RACK1 in the induction of embryonic genes during cardiac hypertrophy/GFs stimulation in a fish heart model, which can be used as an alternative study model for mammals.

Cell death constitutes a critical component of the pathophysiology of cardiovascular diseases. A growing array of non-apoptotic forms of regulated cell death (RCD)-such as necroptosis, ferroptosis, pyroptosis, and cuproptosis-has been identified and is intimately linked to various cardiovascular conditions. These forms of RCD are governed by genetically programmed mechanisms within the cell, with epigenetic modifications being a common and crucial regulatory method. Such modifications include DNA methylation, RNA methylation, histone methylation, histone acetylation, and non-coding RNAs. This review recaps the roles of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs in cardiovascular diseases, as well as the mechanisms by which epigenetic modifications regulate key proteins involved in cell death. Furthermore, we systematically catalog the existing epigenetic pharmacological agents targeting novel forms of RCD and their mechanisms of action in cardiovascular diseases. This article aims to underscore the pivotal role of epigenetic modifications in precisely regulating specific pathways of novel RCD in cardiovascular diseases, thus offering potential new therapeutic avenues that may prove more effective and safer than traditional treatments.

Small non-coding ribonucleic acids (sncRNAs) play an important role in cell regulation and are closely related to the pathogenesis of heart diseases. However, the role and molecular mechanism of transfer RNA-derived small RNAs (tsRNAs) in myocardial fibrosis after myocardial infarction (MI) remain unknown. In this study, we identified and validated sncRNAs (mainly miRNA and tsRNA) associated with myocardial fibrosis after MI through PANDORA sequencing of rat myocardial tissue. As a key enzyme of N4-acetylcytidine (ac4C) acetylation modification, N-acetyltransferase 10 (NAT10) plays an important role in regulating messenger RNA (mRNA) stability and translation efficiency. We found that NAT10 is highly expressed in infarcted myocardial tissue, and the results of acetylated RNA immunoprecipitation sequencing (acRIP-seq) analysis suggest that early growth response 3 (EGR3) may be an important molecule in the pathogenesis of NAT10-mediated myocardial fibrosis. Both in vivo and in vitro experiments have shown that inhibition of NAT10 can reduce the expression of EGR3 and alleviate myocardial fibrosis after MI. tsRNA can participate in gene regulation by inhibiting target genes. The expression of tsr007330 was decreased in myocardial infarction tissue. We found that overexpression of tsr007330 in rat myocardial tissue could antagonize NAT10, improve myocardial function in MI and alleviate myocardial fibrosis. In conclusion, tsRNAs (rno-tsr007330) may regulate the occurrence of myocardial fibrosis by regulating NAT10-mediated EGR3 mRNA acetylation. This study provides new insights into the improvement of myocardial fibrosis after MI by targeting tsRNA therapy.

The adult heart is a complex, multicellular organ that is subjected to a series of regulatory stimuli and circuits and has poor reparative potential. Despite progress in our understanding of disease mechanisms and in the quality of health care, ischaemic heart disease remains the leading cause of death globally, owing to adverse cardiac remodelling, leading to ischaemic cardiomyopathy and heart failure. Therapeutic targets are urgently required for the protection and repair of the ischaemic heart. Moreover, personalized clinical biomarkers are necessary for clinical diagnosis, medical management and to inform the individual response to treatment. Non-coding RNAs (ncRNAs) deeply influence cardiovascular functions and contribute to communication between cells in the cardiac microenvironment and between the heart and other organs. As such, ncRNAs are candidates for translation into clinical practice. However, ncRNA biology has not yet been completely deciphered, given that classes and modes of action have emerged only in the past 5 years. In this Review, we discuss the latest discoveries from basic research on ncRNAs and highlight both the clinical value and the challenges underscoring the translation of these molecules as biomarkers and therapeutic regulators of the processes contributing to the initiation, progression and potentially the prevention or resolution of ischaemic heart disease and heart failure.

Pathological cardiac hypertrophy often precedes heart failure due to various stimuli, yet effective clinical interventions remain limited. Recently, microRNAs (miRNAs) have been identified as critical regulators of cardiovascular development. In this study, we investigated the role of miR-146b-5p and its underlying mechanisms of action in cardiac hypertrophy. Isoprenaline (ISO) treatment induced significant hypertrophy and markedly enhanced the expression of miR-146b-5p in cultured neonatal rat cardiomyocytes and hearts of C57BL/6 mice. Transfection with the miR-146b-5p mimic led to cardiomyocyte hypertrophy accompanied by autophagy inhibition. Conversely, miR-146b-5p inhibition significantly alleviated ISO-induced autophagy depression, thereby mitigating cardiac hypertrophy both in vitro and in vivo. Our results showed that the autophagy-related mediator double FYVE domain-containing protein 1 (DFCP1) is a target of miR-146b-5p. MiR-146b-5p blocked autophagic flux in cardiomyocytes by suppressing DFCP1, thus contributing to hypertrophy. These findings revealed that miR-146b-5p is a potential regulator of autophagy associated with the onset of cardiac hypertrophy, suggesting a possible therapeutic strategy involving the inhibition of miR-146b-5p.

Cardiovascular diseases (CVDs) pose a significant burden on global health. Developing effective diagnostic, therapeutic, and prognostic indicators for CVDs is critical. This narrative review explores the role of select non-coding RNAs (ncRNAs) and provides an in-depth exploration of the roles of miRNAs, lncRNAs, and circRNAs in different aspects of CVDs, offering insights into their mechanisms and potential clinical implications. The review also sheds light on the diverse functions of ncRNAs, including their modulation of gene expression, epigenetic modifications, and signaling pathways. It comprehensively analyzes the interplay between ncRNAs and cardiovascular health, paving the way for potential novel interventions. Finally, the review provides insights into the methodologies used to investigate ncRNA-mediated gene regulation in CVDs, as well as the implications and challenges associated with translating ncRNA research into clinical applications. Considering the broader implications, this research opens avenues for interdisciplinary collaborations, enhancing our understanding of CVDs across scientific disciplines.

Numerous studies have demonstrated that microRNAs (miRNAs) are critically important for the prediction, diagnosis, and characterization of diseases. However, identifying miRNA-disease associations through traditional biological experiments is both costly and time-consuming. To further explore these associations, we proposed a model based on hybrid high-order moments combined with element-level attention mechanisms (HHOMR). This model innovatively fused hybrid higher-order statistical information along with structural and community information. Specifically, we first constructed a heterogeneous graph based on existing associations between miRNAs and diseases. HHOMR employs a structural fusion layer to capture structure-level embeddings and leverages a hybrid high-order moments encoder layer to enhance features. Element-level attention mechanisms are then used to adaptively integrate the features of these hybrid moments. Finally, a multi-layer perceptron is utilized to calculate the association scores between miRNAs and diseases. Through five-fold cross-validation on HMDD v2.0, we achieved a mean AUC of 93.28%. Compared with four state-of-the-art models, HHOMR exhibited superior performance. Additionally, case studies on three diseases-esophageal neoplasms, lymphoma, and prostate neoplasms-were conducted. Among the top 50 miRNAs with high disease association scores, 46, 47, and 45 associated with these diseases were confirmed by the dbDEMC and miR2Disease databases, respectively. Our results demonstrate that HHOMR not only outperforms existing models but also shows significant potential in predicting miRNA-disease associations.

MicroRNAs, involved in a large variety of pathological conditions, tend to be potential specific biomarkers in cardiovascular diseases. Moreover, these short, non-coding RNAs, regulate post-transcriptional gene expression and protein synthesis, making them ideal for therapeutic targets. Down-regulation and up-regulation of specific microRNAs are currently studied as a novel approach to the diagnosis and treatment of cardiovascular diseases, such as chronic and acute coronary syndromes, atherosclerosis, heart failure, and arrhythmia. MicroRNAs are interesting and attractive targets for cardiovascular-associated therapeutics because of their stability, tissue-specific expression pattern, and secretion of body fluids. Extended research on their isolation, detection, and function will provide the standardization needed for using microRNAs as biomarkers and potential therapeutic targets. This review will summarize recent data on the implication of microRNAs in cardiovascular diseases, their potential role as biomarkers for diagnosis, and also the challenges of using microRNAs as future therapeutic targets.

Physical exercise has been widely acknowledged as a beneficial lifestyle alteration and a potent non-pharmacological treatment for heart disease. Extensive investigations have revealed the beneficial effects of exercise on the heart and the underlying mechanisms involved. Exercise is considered one of the key factors that can lead to epigenetic alterations. The increasing number of identified molecules in the exercised heart has led to many studies in recent years that have explored the cellular function of ncRNAs and RNA modifications in the heart. Investigating the regulatory role of RNA-mediated epigenetic regulation in exercised hearts will contribute to the development of therapeutic strategies for the management of heart diseases. This review aims to summarize the positive impact of exercise on cardiac health. We will first provide an overview of the mechanisms through which exercise offers protection to the heart. Subsequently, we will delve into the current understanding of ncRNAs, specifically miRNAs, lncRNAs, and circRNAs, as well as RNA modification, focusing on RNA m6A and RNA A-to-I editing, and how they contribute to exercise-induced benefits for the heart. Lastly, we will explore the emerging therapeutic strategies that utilize exercise-mediated RNA epigenetic regulation in the treatment of heart diseases, while also addressing the challenges faced in this field.

Cardiac hypertrophy, worldwide known as an adaptive functional compensatory state of myocardial stress, is mainly believed to proceed to severe heart diseases, even to sudden death. Emerging studies have explored the microRNA alteration during hypertrophy. However, the mechanisms of microRNAs involved in cardiac hypertrophy are still uncertain. We studied young rats to establish abdominal aorta coarctation (AAC) for 4 weeks. With the significant downregulated cardiac function and upregulated hypertrophic biomarkers, AAC-induced rats showed enlarged myocardiocytes and alterations in microRNAs, especially downregulated miR-31-5p. miR-31-5p targets the 3'UTR of Nfatc2ip and inhibits myocardial hypertrophy in vitro and in vivo. Furthermore, we verified that Nfatc2ip is necessary and sufficient for cardiac hypertrophy in neonatal rat cardiomyocytes. Moreover, we found miR-31-5p inhibited the colocalization of Nfatc2ip and hypertrophic gene β-Mhc. Luciferase assay and ChiP-qPCR test demonstrated that Nfatc2ip binded to the core-promoter of β-Mhc and enhanced its transcriptional activity. Above all, our study found a new pathway, mir-31-5p/Nfatc2ip/β-Mhc, which is involved in cardiac hypertrophy, suggesting a potential target for intervention of cardiac hypertrophy.

CircRNAs are a class of single-stranded RNAs characterized by covalently looped structures. Emerging advances have promoted our understanding of circRNA biogenesis, nuclear export, biological functions, and functional mechanisms. Roles of circRNAs in diverse diseases have been increasingly recognized in the past decade, with novel approaches in bioinformatics analysis and new strategies in modulating circRNA levels, which have made circRNAs the hot spot for therapeutic applications. Moreover, due to the intrinsic features of circRNAs such as high stability, conservation, and tissue-/stage-specific expression, circRNAs are believed to be promising prognostic and diagnostic markers for diseases. Aiming cardiovascular disease (CVD), one of the leading causes of mortality worldwide, we briefly summarize the current understanding of circRNAs, provide the recent progress in circRNA functions and functional mechanisms in CVD, and discuss the future perspectives both in circRNA research and therapeutics based on existing knowledge.

Despite the great progress in diagnosis, prevention, and treatment, cardiovascular diseases (CVDs) are still the most prominent cause of death worldwide [...].

The main pathogenic factor leading to cardiac remodeling and heart failure is myocardial fibrosis. Recent research indicates that microRNAs are essential for the progress of cardiac fibrosis. Myocardial fibrosis is considered to be alleviated through the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), which does this by blocking the transforming growth factor β1 (TGF-β1) signaling pathway. Here, this study sought to elucidate the post-transcriptional regulation of miR-19a-3p on BAMBI and its role in TGF-β1-induced cardiac fibroblast activation. Transverse aortic constriction (TAC) caused both myocardial interstitial and perivascular collagen deposition. RT-PCR showed that miR-19a-3p was upregulated in the myocardial tissue of cardiac fibrosis, and TGF-β1 induced an increase of miR-19a-3p expression in cardiac fibroblasts. The dual-luciferase reporter test and qRT-PCR confirmed that miR-19a-3p directly combined with BAMBI mRNA 3'UTR, thus reduced BAMBI expression, which diminished the capability of BAMBI to inhibit TGF-β1. Furthermore, miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling, which supported cardiac fibroblast activation, which blocked by overexpression of BAMBI. These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI, further boosting the activation of cardiac fibroblasts, and may thus offer a novel strategy to tackling myocardial fibrosis.

The risk of developing pulmonary hypertension (PH) in people living with HIV is at least 300-fold higher than in the general population, and illicit drug use further potentiates the development of HIV-associated PH. The relevance of extracellular vesicles (EVs) containing both coding as well as non-coding RNAs in PH secondary to HIV infection and drug abuse is yet to be explored. We here compared the miRNA cargo of plasma-derived EVs from HIV-infected stimulant users with (HIV + Stimulants + PH) and without PH (HIV + Stimulants) using small RNA sequencing. The data were compared with 12 PH datasets available in the GEO database to identify potential candidate gene targets for differentially altered miRNAs using the following functional analysis tools: ingenuity pathway analysis (IPA), over-representation analysis (ORA), and gene set enrichment analysis (GSEA). MiRNAs involved in promoting cell proliferation and inhibition of intrinsic apoptotic signaling pathways were among the top upregulated miRNAs identified in EVs from the HIV + Stimulants + PH group compared to the HIV + Stimulants group. Alternatively, the downregulated miRNAs in the HIV + Stimulants + PH group suggested an association with the negative regulation of smooth muscle cell proliferation, IL-2 mediated signaling, and transmembrane receptor protein tyrosine kinase signaling pathways. The validation of significantly differentially expressed miRNAs in an independent set of HIV-infected (cocaine users and nondrug users) with and without PH confirmed the upregulation of miR-32-5p, 92-b-3p, and 301a-3p positively regulating cellular proliferation and downregulation of miR-5571, -4670 negatively regulating smooth muscle proliferation in EVs from HIV-PH patients. This increase in miR-301a-3p and decrease in miR-4670 were negatively correlated with the CD4 count and FEV1/FVC ratio, and positively correlated with viral load. Collectively, this data suggest the association of alterations in the miRNA cargo of circulating EVs with HIV-PH.

Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood. Data in humans is confounded by age and co-morbidities. We investigated the effects of ovariectomy and estrogen replacement on the left ventricular (LV) gene expression of pro-inflammatory and pro-fibrotic factors involved in HFpEF and putative regulating miRNAs. Nine-week-old C57BL/6 female mice were subjected to ovariectomy (OVX) or SHAM operation. OVX and SHAM groups were sacrificed 1-, 6-, and 12-weeks post-surgery (T1/SHAM; T1/OVX; T6/SHAM; T6/OVX, T12/SHAM). 17β-estradiol (E2) or vehicle (VEH) was then administered to the OVX groups for 6 weeks (T12/OVX/E2; T12/OVX/VEH). Another SHAM group was sacrificed 12-weeks post-surgery. RNA and miRNAs were extracted from the LV apex. An early 3-fold increase in the gene expression of IL-1α, IL-6, Mmp9, Mmp12, Col1α1, and Col3α1 was observed one-week post-surgery in T1/OVX vs. T1/SHAM, but not at later time points. miRNA-26a was lower in T1/OVX vs. T1/SHAM and was inversely correlated with Col1α1 and Col3α1 expression 1-week post-surgery (r = -0.79 p < 0.001; r = -0.6 p = 0.007). miRNAs-26a, 29b, and 133a were significantly higher, while Col1α1, Col3α1, IL-1α, IL-6, Tnfα, Mmp12, and FasL gene expression was significantly lower in E2- compared to vehicle-treated OVX mice. miRNA-26a was inversely correlated with Col3α1 in T12/OVX/ E2 (r = -0.56 p = 0.02). OVX triggered an early increase in the gene expression of pro-inflammatory and pro-fibrotic factors, highlighting the importance of the early phase post-cessation of ovarian function. E2 replacement therapy, even if it was not immediately initiated after OVX, reversed these unfavorable changes and upregulated cardiac miRNA-26a, previously unknown to be affected by menopausal status.

MicroRNA (miRNA), crucial non-coding RNAs, have emerged as key biomarkers in molecular diagnostics, prognosis, and personalized medicine due to their significant role in gene expression regulation. Salivary miRNA, in particular, stands out for its non-invasive collection method and ease of accessibility, offering promising avenues for the development of point-of-care diagnostics for a spectrum of diseases, including cancer, neurodegenerative disorders, and infectious diseases. Such development promises rapid and precise diagnosis, enabling timely treatment. Despite significant advancements in salivary miRNA-based testing, challenges persist in the quantification, multiplexing, sensitivity, and specificity, particularly for miRNA at low concentrations in complex biological mixtures. This work delves into these challenges, focusing on the development and application of salivary miRNA tests for point-of-care use. We explore the biogenesis of salivary miRNA and analyze their quantitative expression and their disease relevance in cancer, infection, and neurodegenerative disorders. We also examined recent progress in miRNA extraction, amplification, and multiplexed detection methods. This study offers a comprehensive view of the development of salivary miRNA-based point-of-care testing (POCT). Its successful advancement could revolutionize the early detection, monitoring, and management of various conditions, enhancing healthcare outcomes. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > Diagnostic Nanodevices.

The use of non-coding RNAs (ncRNAs) as drug targets is being researched due to their discovery and their role in disease. Targeting ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is an attractive approach for treating various diseases, such as cardiovascular disease and cancer. This seminar discusses the current status of ncRNAs as therapeutic targets in different pathological conditions. Regarding miRNA-based drugs, this approach has made significant progress in preclinical and clinical testing for cardiovascular diseases, where the limitations of conventional pharmacotherapy are evident. The challenges of miRNA-based drugs, including specificity, delivery, and tolerability, will be discussed. New approaches to improve their success will be explored. Furthermore, it extensively discusses the potential development of targeted therapies for cardiovascular disease. Finally, this document reports on the recent advances in identifying and characterizing microRNAs, manipulating them, and translating them into clinical applications. It also addresses the challenges and perspectives towards clinical application.

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.

Cardiovascular disease (CVD) is a serious public health concern whose incidence has been on a rise and is projected by the World Health Organization to be the leading global cause of mortality by 2030. Heart failure (HF) is a complicated syndrome resulting from various CVDs of heterogeneous etiologies and exhibits varying pathophysiology, including activation of inflammatory signaling cascade, apoptosis, fibrotic pathway, and neuro-humoral system, thereby leading to compromised cardiac function. During this process, several biomolecules involved in the onset and progression of HF are released into circulation. These circulating biomolecules could serve as unique biomarkers for the detection of subclinical changes and can be utilized for monitoring disease severity. Hence, it is imperative to identify these biomarkers to devise an early predictive strategy to stop the deterioration of cardiac function caused by these complex cellular events. Furthermore, measurement of multiple biomarkers allows clinicians to divide HF patients into sub-groups for treatment and management based on early health outcomes. The present article provides a comprehensive overview of current omics platform available for discovering biomarkers for HF management. Some of the existing and novel biomarkers for the early detection of HF with special reference to endothelial biology are also discussed.

Cardiovascular and metabolic diseases such as hypertension, type 2 diabetes, and obesity develop long-term fibrotic processes in the heart, promoting pathological cardiac remodeling, including after myocardial infarction, reparative fibrotic processes also occur. These processes are regulated by many intracellular signaling pathways that have not yet been completely elucidated, including those associated with microRNA (miRNA) expression. miRNAs are small RNA transcripts (18-25 nucleotides in length) that act as posttranscriptionally regulators of gene expression, inhibiting or degrading one or more target messenger RNAs (mRNAs), and proven to be involved in many biological processes such as cell cycle, differentiation, proliferation, migration, and apoptosis, directly affecting the pathophysiology of several diseases, including cardiac fibrosis. Exercise training can modulate the expression of miRNAs and it is known to be beneficial in various cardiovascular diseases, attenuating cardiac fibrosis processes. However, the signaling pathways modulated by the exercise associated with miRNAs in cardiac fibrosis were not fully understood. Thus, this review aims to analyze the expression of miRNAs that modulate signaling pathways in cardiac fibrosis processes that can be regulated by exercise training.

Background: Despite surgical advances, children with tetralogy of Fallot/pulmonary atresia/major aortopulmonary collaterals (TOF/PA/MAPCAs) are subject to chronic right ventricular (RV) pressure and volume overload. Current diagnostic tools do not identify adverse myocardial remodeling and cannot predict progression to RV failure. We sought to identify a noninvasive, circulating signature of the systemic response to right heart stress to follow disease progression. Methods: Longitudinal data were collected from patients with TOF/PA/MAPCAs (N = 5) at the time of (1) early RV pressure overload and (2) late RV pressure and volume overload. Plasma protein and microRNA expression were evaluated using high-throughput data-independent mass spectroscopy and Agilent miR Microarray, respectively. Results: At the time of early RV pressure overload, median patient age was 0.34 years (0.02-9.37), with systemic RV pressures, moderate-severe hypertrophy, and preserved systolic function. Late RV pressure and volume overload occurred at a median age of 4.08 years (1.51-10.83), with moderate RV hypertrophy and dilation, and low normal RV function; 277 proteins were significantly dysregulated (log2FC ≥0.6/≤-0.6, FDR≤0.05), predicting downregulation in lipid transport (apolipoproteins), fibrinolytic system, and extracellular matrix structural proteins (talin 1, profilin 1); and upregulation in the respiratory burst. Increasing RV size and decreasing RV function correlated with decreasing structural protein expression. Similarly, miR expression predicted downregulation of extracellular matrix-receptor interactions and upregulation in collagen synthesis. Conclusion: To our knowledge, we show for the first time a noninvasive protein and miR signature reflecting the systemic response to adverse RV myocardial remodeling in TOF/PA/MAPCAs which could be used to follow disease progression.

Non-coding RNAs (ncRNAs) are a heterogeneous group of transcripts that, by definition, are not translated into proteins. Since their discovery, ncRNAs have emerged as important regulators of multiple biological functions across a range of cell types and tissues, and their dysregulation has been implicated in disease. Notably, much research has focused on the link between microRNAs (miRNAs) and human cancers, although other ncRNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are also emerging as relevant contributors to human disease. In this Review, we summarize our current understanding of the roles of miRNAs, lncRNAs and circRNAs in cancer and other major human diseases, notably cardiovascular, neurological and infectious diseases. Further, we discuss the potential use of ncRNAs as biomarkers of disease and as therapeutic targets.

Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear.

A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway.

Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3).

Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.