RNA Therapeutics for Treatment of Cardiovascular Diseases

Lucas, Tina; Dimmeler, Stefanie

doi:10.1161/circresaha.116.308730

Cited by 20 publications

(5 citation statements)

References 15 publications

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“…We demonstrate a specific profile of deregulated miRNAs in vascular tissue from a rat model of elevated vascular shear stress and indicate significant correlations and predicted interactions of these miRNAs with genes that regulate angiogenesis. Our study extends the current understanding of miRNA-regulated pathways in flow-stimulated angiogenesis and identifies several promising targets for future studies on RNA-based therapeutic interventions [81]. Future translational research in this field may deliver new therapeutic approaches for miRNA-driven enhancement of local angiogenesis, aimed at either rescuing critically ischemic tissue e.g.…”

Section: Discussionmentioning

confidence: 55%

MicroRNA-regulated pathways of flow-stimulated angiogenesis and vascular remodeling in vivo

et al. 2019

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BackgroundVascular shear stress promotes endothelial cell sprouting in vitro. The impact of hemodynamic forces on microRNA (miRNA) and gene expression within growing vascular networks in vivo, however, remain poorly investigated. Arteriovenous (AV) shunts are an established model for induction of neoangiogenesis in vivo and can serve as a tool for analysis of hemodynamic effects on miRNA and gene expression profiles over time.MethodsAV shunts were microsurgically created in rats and explanted on postoperative days 5, 10 and 15. Neoangiogenesis was confirmed by histologic analysis and micro-computed tomography. MiRNA and gene expression profiles were determined in tissue specimens from AV shunts by microarray analysis and quantitative real-time polymerase chain reaction and compared with sham-operated veins by bioinformatics analysis. Changes in protein expression within AV shunt endothelial cells were determined by immunohistochemistry.ResultsSamples from AV shunts exhibited a strong overexpression of proangiogenic cytokines, oxygenation-associated genes (HIF1A, HMOX1), and angiopoetic growth factors. Significant inverse correlations of the expressions of miR-223-3p, miR-130b-3p, miR-19b-3p, miR-449a-5p, and miR-511-3p which were up-regulated in AV shunts, and miR-27b-3p, miR-10b-5p, let-7b-5p, and let-7c-5p, which were down-regulated in AV shunts, with their predicted interacting targets C–X–C chemokine receptor 2 (CXCR2), interleukin-1 alpha (IL1A), ephrin receptor kinase 2 (EPHA2), synaptojanin-2 binding protein (SYNJ2BP), forkhead box C1 (FOXC1) were present. CXCL2 and IL1A overexpression in AV shunt endothelium was confirmed at the protein level by immunohistochemistry.ConclusionsOur data indicate that flow-stimulated angiogenesis is determined by an upregulation of cytokines, oxygenation associated genes and miRNA-dependent regulation of FOXC1, EPHA2 and SYNJ2BP.Electronic supplementary materialThe online version of this article (10.1186/s12967-019-1767-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 55%

MicroRNA-regulated pathways of flow-stimulated angiogenesis and vascular remodeling in vivo

et al. 2019

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“…MiRs can be inhibited by different types of antisense RNAs (antimiRs) including phosphothioate-modified antisense RNAs that are linked to cholesterol for enhanced uptake of the oligonucleotide or locked nucleotide acids DNA mixmers1. Such antisense oligonucleotides are relatively easily taken up by detoxifying organs such as the liver or kidney, but uptake in other organs such as the muscle or brain tends to be limited23. Local delivery or activation may be necessary to augment the biological functions of antimiRs in the target tissue and reduce systemic toxicity.…”

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confidence: 99%

Light-inducible antimiR-92a as a therapeutic strategy to promote skin repair in healing-impaired diabetic mice

et al. 2017

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MicroRNAs (miRs) are small non-coding RNAs that post-transcriptionally control gene expression. Inhibition of miRs by antisense RNAs (antimiRs) might be a therapeutic option for many diseases, but systemic inhibition can have adverse effects. Here we show that light-activatable antimiRs efficiently and locally restricted target miR activity in vivo. We use an antimiR-92a and establish a therapeutic benefit in diabetic wound healing. AntimiR-92a is modified with photolabile protecting groups, so called ‘cages'. Irradiation activates intradermally injected caged antimiR-92a without substantially affecting miR-92a expression in other organs. Light activation of caged antimiR-92a improves healing in diabetic mice to a similar extent as conventional antimiRs and derepresses the miR-92a targets Itga5 and Sirt1, thereby regulating wound cell proliferation and angiogenesis. These data show that light can be used to locally activate therapeutically active antimiRs in vivo.

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“…To overcome these limitations, microRNA mimics can be chemically modified to be more specific, stable, and efficient. Linking these to RNA molecules able to specifically bind to target receptors, known as aptamers, is another strategy to increase cell-type-specific uptake [ 24 , 118 ].…”

Section: Therapeutic Delivery Of Drugs Targeting Non-coding Rnasmentioning

confidence: 99%

Non-Coding RNAs in the Therapeutic Landscape of Pathological Cardiac Hypertrophy

Silva

Martins

2022

Cells

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Cardiovascular diseases are a major health problem, and long-term survival for people diagnosed with heart failure is, still, unrealistic. Pathological cardiac hypertrophy largely contributes to morbidity and mortality, as effective therapeutic approaches are lacking. Non-coding RNAs (ncRNAs) arise as active regulators of the signaling pathways and mechanisms that govern this pathology, and their therapeutic potential has received great attention in the last decades. Preclinical studies in large animal models have been successful in ameliorating cardiac hypertrophy, and an antisense drug for the treatment of heart failure has, already, entered clinical trials. In this review, we provide an overview of the molecular mechanisms underlying cardiac hypertrophy, the involvement of ncRNAs, and the current therapeutic landscape of oligonucleotides targeting these regulators. Strategies to improve the delivery of such therapeutics and overcome the actual challenges are, also, defined and discussed. With the fast advance in the improvement of oligonucleotide drug delivery, the inclusion of ncRNAs-targeting therapies for cardiac hypertrophy seems, increasingly, a closer reality.

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RNA Therapeutics for Treatment of Cardiovascular Diseases

Cited by 20 publications

References 15 publications

MicroRNA-regulated pathways of flow-stimulated angiogenesis and vascular remodeling in vivo

MicroRNA-regulated pathways of flow-stimulated angiogenesis and vascular remodeling in vivo

Light-inducible antimiR-92a as a therapeutic strategy to promote skin repair in healing-impaired diabetic mice

Non-Coding RNAs in the Therapeutic Landscape of Pathological Cardiac Hypertrophy

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