The discovery of thousands of noncoding RNAs (ncRNAs) has expanded our view on mammalian genomes and transcriptomes, as well as their organization and regulation. Accumulating evidence on aberrantly ...regulated ncRNAs, including short microRNAs, long ncRNAs and circular RNAs, across various heart diseases indicates that ncRNAs are critical contributors to cardiovascular pathophysiology. In addition, ncRNAs are released into the circulation where they are present in concentration levels that differ between healthy subjects and diseased patients. Although little is known about the origin and function of such circulating ncRNAs, these molecules are increasingly recognized as noninvasive and readily accessible biomarker for risk stratification, diagnosis and prognosis of cardiac injury, and multiple forms of cardiovascular disease. In this review, we summarize recent findings on biological characteristics of circulating ncRNAs and highlight their value as potential biomarker in selected pathologies of cardiovascular disease.
RNAs not encoding proteins have gained prominence over the last couple of decades as fundamental regulators of cellular function. Not surprisingly, their dysregulation is increasingly being linked to ...pathology. Here, we review recent reports investigating the pathophysiological relevance of this species of RNA for the cardiovascular system, concentrating mainly on recent findings on long noncoding RNAs and microRNAs in cardiac hypertrophy and failure.
Heart failure is a leading cause of death in industrialized nations especially in an aging population. The recent improvements in cardiac revascularization therapy reduced death rates because of ...myocardial infarction but steadily increased the number of individuals developing cardiac remodeling and heart failure in the future. Conceptual novel approaches entering the clinics to treat cardiac remodeling and heart failure remain scarce. MicroRNAs emerged as powerful and dynamic modifiers of cardiovascular diseases. In this review, the current approaches using microRNAs as novel diagnostic and therapeutic strategies for cardiac remodeling and heart failure are highlighted. Other gene regulatory mechanisms presented include long (>200 bp) noncoding RNAs that function as an additional regulatory machinery of the genome controlling both transcriptional and post-transcriptional events also in the cardiovascular system.
Vast parts of mammalian genomes encode for transcripts that are not further translated into proteins. The purpose of the majority of such noncoding ribonucleic acids (RNAs) remained paradoxical for a ...long time. However, a growing body of evidence demonstrates that long noncoding RNAs are dynamically expressed in different cell types, diseases, or developmental stages to execute a wide variety of regulatory roles at virtually every step of gene expression and translation. Indeed, long noncoding RNAs influence gene expression via epigenetic modulations, through regulating alternative splicing, or by acting as molecular sponges. The abundance of long noncoding RNAs in the cardiovascular system indicates that they may be part of a complex regulatory network governing physiology and pathology of the heart. In this review, we discuss the multifaceted functions of long noncoding RNAs and highlight the current literature with an emphasis on cardiac development and disease. Furthermore, as the enormous spectrum of long noncoding RNAs potentially opens up new avenues for diagnosis and prevention of heart failure, we ultimately evaluate the futuristic prospects of long noncoding RNAs as biomarkers, and therapeutic targets for the treatment of cardiovascular disorders, as well.
Advances in RNA-sequencing techniques have led to the discovery of thousands of non-coding transcripts with unknown function. There are several types of non-coding linear RNAs such as microRNAs ...(miRNA) and long non-coding RNAs (lncRNA), as well as circular RNAs (circRNA) consisting of a closed continuous loop. This review guides the reader through important aspects of non-coding RNA biology. This includes their biogenesis, mode of actions, physiological function, as well as their role in the disease context (such as in cancer or the cardiovascular system). We specifically focus on non-coding RNAs as potential therapeutic targets and diagnostic biomarkers.
Oligonucleotide therapeutics are a novel promising class of drugs designed to specifically target either coding or non-coding RNA molecules to revolutionize treatment of various diseases. During ...preclinical development, investigations of the pharmacokinetic characteristics of these oligonucleotide-based drug candidates are essential. Oligonucleotides possess a long history of chemical modifications to enhance their stability and binding affinity, as well as reducing toxicity. Phosphorothioate backbone modifications of oligonucleotides were a hallmark of this development process that greatly enhanced plasma stability and protein binding of these agents. Modifications such as 2′-O-methylation further improved stability, while other modifications of the ribose, such as locked nucleic acid (LNA) modification, significantly increased binding affinity, potency, and tissue half-life. These attributes render oligonucleotide therapeutics able to regulate protein expression in both directions depending on the target RNA. Thus, a growing interest has emerged using these oligonucleotides in the treatment of neurodegenerative and cardiac disorders as well as cancer, since the deregulation of certain coding and non-coding RNAs plays a key role in the development of these diseases. Cutting edge research is being performed in the field of non-coding RNAs, identifying potential therapeutic targets, and developing novel oligonucleotide-based agents that outperform classical drugs. Some of these agents are either in clinical trials showing promising results or are already US Food and Drug Administration (FDA) approved, with more oligonucleotides being developed for therapeutic purposes. This is the advent of mechanism-based next-generation therapeutics for a wide range of diseases.
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Oligonucleotide therapeutics are a promising class of drugs designed to target RNA molecules to revolutionize treatment of many diseases, including neurodegenerative and cardiac disorders as well as cancer, since specific targeting of coding and non-coding RNAs may outperform classical drug-based approaches.
Cardiovascular diseases are a major cause of human morbidity and mortality, posing a high socioeconomic burden on the health sector worldwide. microRNAs (miRNAs) constitute a new class of unique ...molecular regulators involved in the pathophysiology of a wide range of disorders. Studies in the past decade have identified miRNA signatures of various cardiovascular disorders and successfully validated miRNA-based therapeutic options in various small and a few large experimental cardiovascular disease models. In these models, researchers manipulate the expression of miRNAs and downstream signaling cascades, aiming to prevent and cure cardiovascular disease. Here, we review and discuss the recent reports on the in vivo use of miRNA animal models and miRNA therapeutic development as well as provide an outlook for clinical applications in the near future.
MicroRNAs (miRNAs) are important regulators of gene expression and fundamentally impact on cardiovascular function in health and disease. A tight control of miRNA expression is crucial for the ...maintenance of tissue homeostasis. However, a comprehensive understanding of the various levels of miRNA regulation is in its infancy. We here summarize the current knowledge about regulation of cardiovascular miRNAs at the transcriptional level by transcription factors, during processing by the Drosha and Dicer complexes and the importance of miRNA modification, editing, and decay mechanisms. As an example, miRNA regulation in diabetic and hypoxic cardiovascular disease conditions is discussed. Better knowledge about regulatory mechanisms of miRNAs in cardiovascular disease will probably lead to improved and novel miRNA-based therapeutic therapies.
During the past decade numerous studies highlighted the importance of long non-coding RNAs (lncRNAs) in orchestrating cardiovascular cell signaling. Classified only by a transcript size of more than ...200 nucleotides and their inability to code for proteins, lncRNAs constitute a heterogeneous group of RNA molecules with versatile functions and interaction partners, thus interfering with numerous endogenous signaling pathways. Intrinsic transcriptional regulation of lncRNAs is not only specific for different cell types or developmental stages, but may also change in response to stress factors or under pathological conditions. Regarding the heart, an increasing number of studies described the critical regulation of lncRNAs in multiple cardiac disorders, underlining their key role in the development and progression of cardiac diseases. In this review article, we will summarize functional cardiac lncRNAs with a detailed view on their molecular mode of action in pathological cardiac remodeling and myocardial infarction. In addition, we will discuss the use of circulating lncRNAs as biomarkers for prognostic and diagnostic purposes and highlight the potential of lncRNAs as a novel class of therapeutic targets for therapeutic purpose in heart diseases.
The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation. The gene ...coding for pri-miR-21 (primary transcript containing miR-21) is located within the intronic region of the TMEM49 gene. Despite pri-miR-21 and TMEM49 are overlapping genes in the same direction of transcription, pri-miR-21 is independently transcribed by its own promoter regions and terminated with its own poly(A) tail. After transcription, primiR- 21 is finally processed into mature miR-21. Expression of miR-21 has been found to be deregulated in almost all types of cancers and therefore was classified as an oncomiR. During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described. MiR-21 additionally regulates various immunological and developmental processes. Due to the critical functions of its target proteins in various signaling pathways, miR-21 has become an attractive target for genetic and pharmacological modulation in various disease conditions.
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