Cardiac fibrosis as a result of excessive extracellular matrix deposition leads to stiffening of the heart, which can eventually lead to heart failure. An important event in cardiac fibrosis is the ...transformation of fibroblasts into myofibroblasts, which secrete large amounts of extracellular matrix proteins. Although the function of protein-coding genes in myofibroblast activation and fibrosis have been a topic of investigation for a long time, it has become clear that noncoding RNAs also play key roles in cardiac fibrosis. This review discusses the involvement of microRNAs and long noncoding RNAs in cardiac fibrosis and summarizes the issues related to translating these findings into real-life therapies.
When considering the pathological steps in the progression from cardiac overload towards the full clinical syndrome of heart failure, it is becoming increasingly clear that the extracellular matrix ...(ECM) is an important determinant in this process. Chronic pressure overload induces a number of structural alterations, not only hypertrophy of cardiomyocytes but also an increase in ECM proteins in the interstitium and perivascular regions of the myocardium. When this culminates in excessive fibrosis, myocardial compliance decreases and electrical conduction is affected. Altogether, fibrosis is associated with an increased risk of ventricular dysfunction and arrhythmias. Consequently, anti-fibrotic strategies are increasingly recognized as a promising approach in the prevention and treatment of heart failure. Thus, dissecting the molecular mechanisms underlying the development of cardiac fibrosis is of great scientific and therapeutic interest. In this review, we provide an overview of the available evidence supporting the general idea that fibrosis plays a causal role in deteriorating cardiac function. Next, we will delineate the signalling pathways importantly governed by transforming growth factor β (TGFβ) in the control of cardiac fibrosis. Finally, we will discuss the recent discovery that miRNAs importantly regulate cardiac fibrosis.
In the past few years, the crucial role of different micro-RNAs (miRNAs) in the cardiovascular system has been widely recognized. Recently, it was discovered that extracellular miRNAs circulate in ...the bloodstream and that such circulating miRNAs are remarkably stable. This has raised the possibility that miRNAs may be probed in the circulation and can serve as novel diagnostic markers. Although the precise cellular release mechanisms of miRNAs remain largely unknown, the first studies revealed that these circulating miRNAs may be delivered to recipient cells, where they can regulate translation of target genes. In this review, we will discuss the nature of the stability of miRNAs that circulate in the bloodstream and discuss the available evidence regarding the possible function of these circulating miRNAs in distant cell-to-cell communication. Furthermore, we summarize and discuss the usefulness of circulating miRNAs as biomarkers for a wide range of cardiovascular diseases such as myocardial infarction, heart failure, atherosclerosis, hypertension, and type 2 diabetes mellitus.
Circular RNAs (circRNAs) are emerging as a new class of non-coding RNA molecules. This unusual class of RNA species is generated by a back-splicing event of one or two exons, resulting in a ...covalently closed circRNA molecule. Owing to their circular form, circRNAs are protected from degradation by exonucleases and have greater stability than linear RNA. Advances in computational analysis of RNA sequencing have revealed that thousands of different circRNAs are expressed in a wide range of mammalian tissues, including the cardiovascular system. Moreover, numerous circRNAs are expressed in a disease-specific manner. A great deal of progress has been made in understanding the biogenesis and function of these circRNAs. In this Review, we discuss the current understanding of circRNA biogenesis and function, with a particular emphasis on the cardiovascular system.
One of the major challenges in cardiovascular disease is the identification of reliable clinical biomarkers that can be routinely measured in plasma. MicroRNAs (miRNAs) were recently discovered to ...circulate in the bloodstream in a remarkably stable form. Because of their stability and often tissue- and disease-specific expression and the possibility to measure them with high sensitivity and specificity, miRNAs are emerging as new diagnostic biomarkers. In this review we will provide an overview of the potential of circulating miRNAs as biomarkers for a wide range of cardiovascular diseases such as coronary artery disease, myocardial infarction, hypertension, heart failure, viral myocarditis, and type-2 diabetes mellitus. Furthermore, we will discuss the challenges with regard to further validation in large patient cohorts, and we will discuss how the measurement of multiple miRNAs simultaneously might improve the accuracy of the diagnostic test.
Circular RNAs in heart failure Devaux, Yvan; Creemers, Esther E.; Boon, Reinier A. ...
European journal of heart failure,
June 2017, Letnik:
19, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Cardiovascular disease, and particularly heart failure, is still a serious health care issue for which novel treatments and biomarkers are needed. The RNA family comprises different subgroups, among ...which the small‐sized microRNAs and the larger long non‐coding RNAs have shown some potential to aid in moving personalized health care of heart failure patients a step forward. Here, members of the Cardiolinc network review the recent findings suggesting that the less well‐known circular RNAs may constitute a novel reservoir of therapeutic targets and biomarkers of heart failure. The knowledge of the mode of biogenesis of circular RNAs will first be reported, followed by a description of different features that make these RNA molecules of interest for the heart failure community. The functions of circular RNAs in the heart will be described, with some emphasis given to their regulation in the failing heart. Circulating in the bloodstream, circular RNAs have appeared as potential biomarkers and recent findings associated with the use of circular RNAs as heart failure biomarkers will be discussed. Finally, some directions for future research will be provided.
RNA-binding motif protein 20 (RBM20) is essential for normal splicing of many cardiac genes, and loss of RBM20 causes dilated cardiomyopathy. Given its role in splicing, we hypothesized an important ...role for RBM20 in forming circular RNAs (circRNAs), a novel class of noncoding RNA molecules.
To establish the role of RBM20 in the formation of circRNAs in the heart.
Here, we performed circRNA profiling on ribosomal depleted RNA from human hearts and identified the expression of thousands of circRNAs, with some of them regulated in disease. Interestingly, we identified 80 circRNAs to be expressed from the titin gene, a gene that is known to undergo highly complex alternative splicing. We show that some of these circRNAs are dynamically regulated in dilated cardiomyopathy but not in hypertrophic cardiomyopathy. We generated RBM20-null mice and show that they completely lack these titin circRNAs. In addition, in a cardiac sample from an RBM20 mutation carrier, titin circRNA production was severely altered. Interestingly, the loss of RBM20 caused only a specific subset of titin circRNAs to be lost. These circRNAs originated from the RBM20-regulated I-band region of the titin transcript.
We show that RBM20 is crucial for the formation of a subset of circRNAs that originate from the I-band of the titin gene. We propose that RBM20, by excluding specific exons from the pre-mRNA, provides the substrate to form this class of RBM20-dependent circRNAs.
The extracellular matrix (ECM) is best known for its function as a structural scaffold for the tissue and more recently as a microenvironment to sequester growth factors and cytokines allowing for ...rapid and localized changes in their activity in the absence of new protein synthesis. In this review, we explore this and additional new aspects of ECM function in mediating cell-to-cell communications. Fibrillar and nonfibrillar components of ECM can limit and facilitate the transport of molecules through the extracellular space while also regulating interstitial hydrostatic pressure. In turn, transmembrane communications via molecules, such as ECM metalloproteinase inducer, thrombospondins, and integrins, can further mediate cell response to extracellular cues and affect ECM composition and tissue remodeling. Other means of cell-to-cell communication include extracellular microRNA transport and its contribution to gene expression in target cells and the nanotube formation between distant cells, which has recently emerged as a novel conduit for intercellular organelle sharing thereby influencing cell survival and function. The information summarized and discussed here are not limited to the cardiovascular ECM but encompass ECM in general with specific references to the cardiovascular system.
Aberrant expression profiles of circulating microRNAs (miRNAs) have been described in various diseases and provide high sensitivity and specificity. We explored circulating miRNAs as potential ...biomarkers in patients with heart failure (HF).
The goal of this study was to determine whether miRNAs allow to distinguish clinical HF not only from healthy controls but also from non-HF forms of dyspnea.
A miRNA array was performed on plasma of 12 healthy controls and 12 HF patients. From this array, we selected 16 miRNAs for a second clinical study in 39 healthy controls and in 50 cases with reports of dyspnea, of whom 30 were diagnosed with HF and 20 were diagnosed with dyspnea attributable to non-HF-related causes. This revealed that miR423-5p was specifically enriched in blood of HF cases and receiver-operator-characteristics (ROC) curve analysis showed miR423-5p to be a diagnostic predictor of HF, with an area under the curve of 0.91 (P<0.001). Five other miRNAs were elevated in HF cases but also slightly increased in non-HF dyspnea cases.
We identify 6 miRNAs that are elevated in patients with HF, among which miR423-5p is most strongly related to the clinical diagnosis of HF. These 6 circulating miRNAs provide attractive candidates as putative biomarkers for HF.
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