Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature 2011; 469: 336-342

ArticleinNature 469(7330):336-42 · January 2011with32 Reads
DOI: 10.1038/nature09783 · Source: PubMed
First recognized as regulators of development in worms and fruitflies, microRNAs are emerging as pivotal modulators of mammalian cardiovascular development and disease. Individual microRNAs modulate the expression of collections of messenger RNA targets that often have related functions, thereby governing complex biological processes. The wideranging functions of microRNAs in the cardiovascular system have provided new perspectives on disease mechanisms and have revealed intriguing therapeutic targets, as well as diagnostics, for a variety of cardiovascular disorders.
    • "Although the total extent of tRNA Phe cleavage reached was only 50% in the case of a 2- fold excess of RNA over DC6, we cannot completely exclude the possibility of the catalytic turnover of the reaction, especially in the case of scenario 2, with more than one conjugate molecule involved in the catalysis, and this aspect requires separate further investigation. To conclude, the perception of the role that regulatory (non-protein coding) RNAs play in normal or pathologically compromised cells [3][4][5][6][7][8]led to a recognition of RNA as one of the most important biological targets for future therapeutic interventions. It was demonstrated that RNAs in cells are involved in the regulation of crucial biological functions, and thus an interference with their expression profiles or alteration of their specificity may play a pivotal role in progression of many pathological conditions (e.g. "
    [Show abstract] [Hide abstract] ABSTRACT: Traditional therapeutic interventions against abnormal gene expression in disease states at the level of expressed proteins are becoming increasingly difficult due to poor selectivity, off-target effects and associated toxicity. Upstream catalytic targeting of specific RNA sequences offers an alternative platform for drug discovery to achieve more potent and selective treatment through antisense interference with disease-relevant RNAs. We report a novel class of catalytic biomaterials, comprising amphipathic RNA-cleaving peptides placed between two RNA recognition motifs, here demonstrated to target the TΨC loop and 3′ acceptor stem of tRNAPhe. These unique peptidyl-oligonucleotide ‘dual’ conjugates (DCs) were created by phosphoramidate or thiol-maleimide conjugation chemistry of a TΨC-targeting oligonucleotide to the N-terminus of the amphipathic peptide sequence, followed by amide coupling of a 3′-acceptor stem-targeting oligonucleotide to the free C-terminal carboxylic acid functionality of the same peptide. Hybridisation of the DCs bearing two spatially-separated recognition motifs with the target tRNAPhe placed the peptide adjacent to a single-stranded RNA region and promoted cleavage within the ‘action radius’ of the catalytic peptide. Up to 100% cleavage of the target tRNAPhe was achieved by the best candidate (i.e. DC6) within 4 h, when conformational flexibility was introduced into the linker regions between the peptide and oligonucleotide components. This study provides the strong position for future development of highly selective RNA-targeting agents that can potentially be used for disease-selective treatment at the level of messenger, micro, and genomic viral RNA.
    Full-text · Article · Oct 2016
    • "miRNAs are approximately 22 nucleotides long, single-stranded non-coding RNAs that play regulatory roles by targeting mRNAs for cleavage resulting in translational repression [8]. miRNAs play essential roles in many physiological and pathophysiological processes, including inflammation and atherosclerosis [36,45,101]. Most miRNAs are found within cells, but some have been detected in bodily fluids including peripheral blood. "
    [Show abstract] [Hide abstract] ABSTRACT: Discovered in 1947, microparticles (MP) represent a group of sub-micron cell-derived particles isolated by high speed centrifugation. Once regarded as cellular ‘trash', in the past decade MP have gained tremendous attention in both basic sciences and medical research both as biomarkers and mediators of infection, injury and response to therapy. Because MP bear cell surface markers derived from parent cells, accumulate in extracellular fluids (plasma, serum, milk, urine, cerebrospinal fluid) MP based tests are being developed commercially as important components in ‘liquid biopsy’ approaches, providing valuable readouts in cardiovascular disease and cancer, as well as stroke, Alzheimer’s disease and Multiple Sclerosis. Importantly, MP have been reported as mobile transport vectors in the intercellular transfer of mRNAs, microRNAs, lipids and proteins. Here we discuss MP structure, properties and functions with particular relevance to neurological and neurovascular diseases.
    Full-text · Article · Aug 2016
    • "One important concept to keep in mind is that miRNA targets are generally not random genes. Recent studies demonstrated that miRNAs selectively regulate genes within the same pathway [97,[131][132][133]. Therefore, it is tempting to speculate that miRNA may not trigger significant nonspecific off targets. "
    [Show abstract] [Hide abstract] ABSTRACT: Cholesterol is important for various neuronal functions in the brain. Brain has elaborate regulatory mechanisms to control cholesterol metabolism that are distinct from the mechanisms in periphery. Interestingly, dysregulation of the cholesterol metabolism is strongly associated with a number of neurodegenerative diseases. MicroRNAs are short non-coding RNAs acting as post-transcriptional gene regulators. Recently, several microRNAs are demonstrated to be involved in regulating cholesterol metabolism in the brain. This article reviews the regulatory mechanisms of cellular cholesterol homeostasis in the brain. In addition, we discuss the role of microRNAs in brain cholesterol metabolism and their potential implications for the treatment of Alzheimer’s disease. This article is part of a special issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
    Article · May 2016
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