Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches

Physiological Reviews, Journal Year: 2016, Volume and Issue: 96(4), P. 1297 - 1325

Published: Aug. 18, 2016

Advances in RNA-sequencing techniques have led to the discovery of thousands non-coding transcripts with unknown function. There are several types linear RNAs such as microRNAs (miRNA) and long (lncRNA), well circular (circRNA) consisting a closed continuous loop. This review guides reader through important aspects RNA biology. includes their biogenesis, mode actions, physiological function, role disease context (such cancer or cardiovascular system). We specifically focus on potential therapeutic targets diagnostic biomarkers.

Language: Английский

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Vascular Smooth Muscle Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease

Physiological Reviews, Journal Year: 2017, Volume and Issue: 97(4), P. 1555 - 1617

Published: Sept. 28, 2017

The cushioning function of large arteries encompasses distension during systole and recoil diastole which transforms pulsatile flow into a steady in the microcirculation. Arterial stiffness, inverse distensibility, has been implicated various etiologies chronic common monogenic cardiovascular diseases is major cause morbidity mortality globally. first components that contribute to arterial stiffening are extracellular matrix (ECM) proteins support mechanical load, while second important vascular smooth muscle cells (VSMCs), not only regulate actomyosin interactions for contraction but mediate also mechanotransduction cell-ECM homeostasis. Eventually, VSMC plasticity signaling both conductance resistance highly relevant physiology normal early aging. This review summarizes current concepts central pressure tensile circumferential stress as key determinants wall remodeling, depending mainly on architecture cytoskeletal focal adhesion, large/small cross-talk gives rise target organ damage, inflammatory pathways leading calcification or atherosclerosis. We further speculate contribution cellular stiffness along tree stiffness. In addition, this provides latest advances identification gene variants affecting stiffening. Now hemodynamic molecular mechanisms have elucidated, complex interplay between ECM, cells, sensors identified, research should study their potential halt reverse development

Language: Английский

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Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives

European Heart Journal, Journal Year: 2017, Volume and Issue: 39(29), P. 2704 - 2716

Published: March 15, 2017

Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well health cardiovascular disease. About 99% of human do not encode proteins, but are transcriptionally active representing broad spectrum RNAs (ncRNAs) with important regulatory structural functions. Non-coding have been identified critical novel regulators risk factors cell functions thus candidates to improve diagnostics prognosis assessment. Beyond this, ncRNAs rapidly emgerging fundamentally therapeutics. On first level, provide therapeutic targets some which entering assessment clinical trials. second new tools were developed from endogenous serving blueprints. Particularly advanced is RNA interference (RNAi) drugs use recently discovered pathways short interfering becoming versatile for efficient silencing protein expression. Pioneering studies include RNAi targeting liver synthesis PCSK9 resulting highly significant lowering LDL cholesterol or transthyretin (TTR) treatment cardiac TTR amyloidosis. Further mimicking actions may arise exploitation molecular interactions accessible conventional pharmacology. We an update on recent developments perspectives diagnostic diseases, including atherosclerosis/coronary disease, post-myocardial infarction remodelling, heart failure.

Language: Английский

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Circulating Noncoding RNAs as Biomarkers of Cardiovascular Disease and Injury

Circulation Research, Journal Year: 2017, Volume and Issue: 120(2), P. 381 - 399

Published: Jan. 19, 2017

The discovery of thousands noncoding RNAs (ncRNAs) has expanded our view on mammalian genomes and transcriptomes, as well their organization regulation. Accumulating evidence aberrantly regulated ncRNAs, including short microRNAs, long ncRNAs circular RNAs, across various heart diseases indicates that are critical contributors to cardiovascular pathophysiology. In addition, released into the circulation where they present in concentration levels differ between healthy subjects diseased patients. Although little is known about origin function such circulating these molecules increasingly recognized noninvasive readily accessible biomarker for risk stratification, diagnosis prognosis cardiac injury, multiple forms disease. this review, we summarize recent findings biological characteristics highlight value potential selected pathologies

Language: Английский

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A landscape of circular RNA expression in the human heart

Cardiovascular Research, Journal Year: 2016, Volume and Issue: unknown, P. cvw250 - cvw250

Published: Dec. 8, 2016

Circular RNA (circRNA) is a newly validated class of single-stranded RNA, ubiquitously expressed in mammalian tissues and possessing key functions including acting as microRNA sponges transcriptional regulators by binding to RNA-binding proteins. While independent studies confirm the expression circRNA various tissue types, genome-wide heart has yet be described detail.We performed deep RNA-sequencing on ribosomal-depleted isolated from 12 human hearts, 25 mouse hearts across 28-day differentiation time-course embryonic stem cell-derived cardiomyocytes. Using purpose-designed bioinformatics tools, we uncovered total 15 318 3017 cardiac within mouse, respectively. Their abundance generally correlates with their cognate linear but selected circRNAs exist at disproportionately higher abundance. Top highly corresponded genes Titin (TTN), RYR2, DMD. The most abundant cardiac-expressed cytoplasmic localized single-exon circSLC8A1-1. longest transcript TTN alone generates up 415 different exonic isoforms, majority (83%) which originates I-band domain. Finally, confirmed RT-PCR, Sanger sequencing single molecule RNA-fluorescence situ hybridization.Our data provide detailed landscape hearts. There high-abundance specific circRNA. These findings open new avenue for future investigation into this emerging RNA.

Language: Английский

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Long Non-coding RNA NEAT1: A Novel Target for Diagnosis and Therapy in Human Tumors

Frontiers in Genetics, Journal Year: 2018, Volume and Issue: 9

Published: Oct. 15, 2018

The nuclear paraspeckle assembly transcript 1 (NEAT1, a long non-coding RNA) is frequently overexpressed in human tumors, and higher NEAT1 expression correlated with worse survival cancer patients. drives tumor initiation progression by modulating the of genes involved regulation cell growth, migration, invasion, metastasis, epithelial-to-mesenchymal transition, stem cell-like phenotype, chemoresistance radioresistance, indicating potential for to be novel diagnostic biomarker therapeutic target. Mechanistically, functions as scaffold RNA molecule interacting EZH2 (a subunit polycomb repressive complex) influence downstream effectors EZH2, it also acts microRNA (miRNA) sponge suppress interactions between miRNAs target mRNAs, affects miR-129 promoting DNA methylation promoter region. Knockdown via small interfering or short hairpin inhibits malignant behavior cells. In this review, we highlight latest insights into pattern, biological roles mechanisms underlying function especially focus on its clinical implication new an attractive cancers.

Language: Английский

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Inhibition of Hypertrophy Is a Good Therapeutic Strategy in Ventricular Pressure Overload

Circulation, Journal Year: 2015, Volume and Issue: 131(16), P. 1435 - 1447

Published: April 21, 2015

H ypertrophic growth of ventricular myocytes is a hallmark feature numerous forms cardiovascular disease. 1 The hypertrophic process complex, involving vast array structural, signaling, transcriptional, electrophysiological, metabolic, and functional events within the growing cell. 2,3ther cellular elements ventricle, fibroblasts, vascular smooth muscle cells, endothelium, also manifest intricate stress responses, resulting in fibrosis, inflammatory cell infiltration, endothelial dysfunction, stiffness.Current thinking holds that these events, reaction heart to host pathological stresses, provide short-term benefit.However, if disease-related remains unchecked, remodeling become maladaptive predispose morbidity mortality. Response by Crozatier Ventura-Clapier on p 1447Among risks conferred hypertrophy are tachyarrhythmia, predisposing sudden cardiac death, transition failure.Ultimately, derive from wholesale reprogramming relative dedifferentiation myocyte, coupled with similar other types.Conventional myocardium compensatory response increases workload demand, serving minimize wall maintain contractile function.However, several lines evidence, preclinical epidemiological, highlight features chronic hypertrophy.Indeed, many instances, suppression load-induced well tolerated. 4Furthermore, left among most robust markers increased risk for developing failure. 5Therefore, we submit warrants careful consideration as therapeutic strategy. Cardiomyocyte Hypertrophy: Comprehensive Reprogramming CellAlthough evidence suggests small fraction cells ventricle capable re-entering cycle, [6][7][8] majority cardiomyocytes postmitotic and, hence, do not retain ability divide.Rather, they respond growing, shrinking, or dying.In context undergo transformation, which entails significant growth.In setting uncontrolled hypertension, example, hypertrophy.Similarly, after myocardial infarction, surviving border remote zones tissue increase size hemodynamic

Language: Английский

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Long Non-coding RNA Structure and Function: Is There a Link?

Frontiers in Physiology, Journal Year: 2018, Volume and Issue: 9

Published: Aug. 24, 2018

RNA has emerged as the prime target for diagnostics, therapeutics and development of personalized medicine. In particular, noncoding RNAs (ncRNAs) that do not encode proteins, display remarkable biochemical versatility. They can fold into complex structures interact with DNA other RNAs, modulating activity, targets or partners multiprotein complexes. Thus, ncRNAs confer regulatory plasticity represent a new layer epigenetic control is dysregulated in disease. Intriguingly, long (lncRNAs, >200 nucleotides length) structural conservation rather than nucleotide sequence seems to be crucial maintaining their function. LncRNAs tend acquire secondary tertiary functions only impose very subtle constraints. present review we will discuss assays employed determine lncRNA configurations. The implications challenges linking function structure design novel therapeutic approaches also analyzed.

Language: Английский

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Circular RNAs: A Novel Class of Functional RNA Molecules with a Therapeutic Perspective

Molecular Therapy, Journal Year: 2019, Volume and Issue: 27(8), P. 1350 - 1363

Published: July 10, 2019

Circular RNAs (circRNAs) are a subclass of non-coding that lack free 3' and 5' ends and, thus, exist as continuous loop RNAs. Such circular transcripts have been identified for thousands genes, regulated in developmental stages pathophysiological conditions, often expressed tissue- or cell-type-specific manner. For long time, were considered aberrant splicing by-products. However, high-throughput transcriptome sequencing focused molecular characterization individual circRNAs uncovered their ubiquity. Evidence emerges suggesting functional molecules. In this review, we illustrate the current knowledge circRNA formation detection methods. We summarize different mechanisms action highlight with specific roles cardiovascular disease. Finally, describe number tools manipulation, which may be exploited circRNA-based therapeutic interventions future.

Language: Английский

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Hematopoietic Deficiency of the Long Noncoding RNA MALAT1 Promotes Atherosclerosis and Plaque Inflammation

Circulation, Journal Year: 2019, Volume and Issue: 139(10), P. 1320 - 1334

Published: Jan. 17, 2019

Background: The majority of the human genome comprises noncoding sequences, which are in part transcribed as long RNAs (lncRNAs). lncRNAs exhibit multiple functions, including epigenetic control gene expression. In this study, effect lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) on atherosclerosis was examined. Methods: determined apolipoprotein E–deficient (Apoe − /− ) MALAT1-deficient (Malat1 −/− mice that were fed with a high-fat diet and by studying regulation plaques. Results: Apoe Malat1 showed increased plaque size infiltration inflammatory CD45 + cells compared +/+ mice. Bone marrow transplantation bone enhanced atherosclerotic lesion formation, suggests hematopoietic mediate proatherosclerotic phenotype. Indeed, isolated from adhesion to endothelial elevated levels proinflammatory mediators. Moreover, myeloid displayed arteries vivo. anti-inflammatory effects attributed reduction microRNA miR-503. expression further significantly decreased plaques normal lower symptomatic versus asymptomatic patients. Lower associated worse prognosis. Conclusions: Reduced augment formation disease. observed mainly caused accumulation cells.

Language: Английский

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