Inhibition of MicroRNA-92a Protects Against Ischemia/Reperfusion Injury in a Large-Animal Model

Hinkel, Rabea; Penzkofer, Daniela; Zühlke, Stephanie; Fischer, Ariane; Husada, Wira; Qiao, Xu; Baloch, Elisabeth; Rooij, Eva van; Zeiher, Andreas M.; Kupatt, Christian; Dimmeler, Stefanie

doi:10.1161/circulationaha.113.001904

Cited by 290 publications

(259 citation statements)

References 23 publications

(13 reference statements)

Supporting

Mentioning

238

Contrasting

Unclassified

Order By: Relevance

“…8 However, catheter-based delivery of anti-miRs to the heart was found to not fully preventing systemic inhibitory effects of the delivered anti-miRs. Future studies, therefore, may address whether optimizing the catheter-based application, for example, also by intramuscular injection of anti-miRs, as it has been done for cell therapy, may provide a more specific enrichment to the heart.…”

Section: Improvement Of the Efficiency And Specificity Of Anti-mirsmentioning

confidence: 99%

RNA Therapeutics for Treatment of Cardiovascular Diseases

Lucas

Dimmeler

2016

Circulation Research

Self Cite

View full text Add to dashboard Cite

Section: Improvement Of the Efficiency And Specificity Of Anti-mirsmentioning

confidence: 99%

RNA Therapeutics for Treatment of Cardiovascular Diseases

Lucas

Dimmeler

2016

Circulation Research

Self Cite

View full text Add to dashboard Cite

“…However, miR-based therapeutics have not yet entered the stage of clinical trials for cardiovascular disorders. But given the very recent successful inhibition of miR-92a in a large-animal model of cardiac ischemia/reperfusion which resulted in a significant reduction of infarct size on the one hand and the pivotal role of miR-92a in vascular diseases on the other hand suggest that inhibition of miR-92a might emerge as a novel, promising therapeutic approach for the treatment of cardiovascular diseases [23] .…”

Section: Research Highlightmentioning

confidence: 99%

MiR-92a – a key player in cardiovascular remodeling

Dutzmann¹,

Daniel

Bauersachs³

et al. 2015

RNA Dis

View full text Add to dashboard Cite

Small non-coding, highly conserved microRNAs (miRs) play a crucial role in gene regulation, especially in post-transcriptional gene silencing, and are important for vascular homeostasis as well as during pathophysiological vascular remodeling processes. MiR-92a is known to attenuate endothelial cell proliferation, and angiogenesis. Conversely, down regulation of miR-92a improves these endothelial cell-dependent processes. We recently showed that inhibition of miR-92a also accelerates the re-endothelialization process and thus prevents neointima formation following wire-induced injury of murine femoral arteries. Thus, inhibition of miR-92a may represent a promising therapeutic strategy for the treatment of vascular diseases. Percutaneous coronary interventions for the treatment of coronary atherosclerosis count to the most frequently performed therapeutic procedures in medicine [1] . The inevitable endovascular injury triggers a healing process of the arterial wall resulting in neointimal hyperplasia and vessel remodeling [2] . Drug-eluting stents with local delivery of anti-proliferative agents are one of the most important achievements of modern interventional cardiology. These stents sufficiently prevent vessel re-narrowing and thereby markedly reduce the rate of repeat revascularization. However, the substances currently used on drug-eluting stent platforms often impair endothelial coverage of stent struts thus initiating a chronic inflammatory process, delaying arterial healing, and increasing the risk of thrombotic events [3] . Hence, the investigation of molecular strategies targeting specifically the function of distinct cell types i.e. smooth muscle cell proliferation without affecting endothelial cell regenerative capacity are coming in the focus of novel treatment approaches. In this context, selective enhancement of endothelial regeneration after vascular injury has recently been shown to prevent neointimal lesion formation [4] . Small non-coding microRNAs (miRs) involved in post-transcriptional gene silencing are known to control several physiological and pathophysiological processes in the vascular wall [5,6] . MiR-92a is a member of the miR-17~92a cluster comprising six mature miRs, which are involved in the regulation of cell proliferation, development, immunity and tumorigenesis. Specifically, miR-92a has been shown to inhibit EC proliferation, angiogenesis, and vascular repair by an attenuation of the expression of validated target genes, i.e. the class III histone deacetylase sirtuin (Sirt)-1, integrin α5 (Itga5), and the flow-induced atheroprotective transcription factors Krüppel-like factor (Klf)-2 and Klf4 [7][8][9][10] .In initial observations, we detected miR-92a expression primarily in EC of uninjured murine vessels. Consecutively, we evaluated the spatiotemporal expression of miR-92a in a mouse model of wire-induced injury of the mouse femoral artery and found miR-92a levels significantly up-regulated in endothelial cells adjacent to the vascular injury site [11] . Following the overexpr...

show abstract

“…15 Similarly, when miR-92a was blocked by a locked nucleic acid-modified anti-miR in a pig model of myocardial infarction, infarct size was significantly reduced by increased angiogenesis and a reduction in inflammation. 16 Circulating members of the miR-17 to 92 cluster, and especially miR-92a, have been shown to be potent biomarkers for cardiovascular disease. miR-92a levels were strongly associated with coronary artery disease in humans.…”

Section: Circulation Researchmentioning

confidence: 99%

MiR-92a

Winther

Lutgens

2014

Circulation Research

View full text Add to dashboard Cite

Editorial During life, our arteries with their 3 layers, numerous curvatures, branch points, and bifurcations, are continuously exposed to different flow and shear stress conditions. At branch points and bifurcations, especially oscillatory shear stress activates the endothelium, making these arterial sites prone to develop atherosclerosis.1,2 The subendothelial deposition and subsequent modification of lipids, such as low-density lipoprotein (LDL), further enhances this vascular inflammation. Along with endothelial activation, both the innate and adaptive immune system come into play, resulting in further recruitment of leukocytes and formation of atherosclerotic plaques. 1,2 Article, see p 434To keep the development of atherosclerosis under control, our arteries are subjected to a tight regulation to maintain their homeostasis. Regulatory RNAs, including micro-RNAs, are powerful post-transcriptional mediators that control vascular homeostasis, and their deregulation can result in aggravation of endothelial dysfunction and aggravation of vascular disease. Micro-RNAs can therefore be considered as potential novel therapeutics to treat cardiovascular disease. 3In this issue of Circulation Research, Loyer et al 4 performed an elegant screening to identify micro-RNAs affecting atherosclerosis, the so-called atheromiRs, in endothelial cells. The authors selected the atheromiRs in in vitro settings using human umbilical vein endothelial cells based on 2 criteria that are highly relevant for the pathogenesis of atherosclerosis: (1) miRs that exhibit a change in expression by exposure to oxidized LDL (oxLDL) under low shear stress and (2) miRs that are not affected by oxLDL exposure under high shear stress conditions. The miR that was most dysregulated and fulfilled these criteria was miR-92a, which was highly expressed in atherosclerosis-prone regions in normocholesterolemic ldlr −/− mice compared with atherosclerosis-resistant regions in these mice. This difference in miR-92a expression was further enhanced when the ldlr −/− mice were fed a diet to induce hypercholesterolemia. 4 Moreover, miR-92a seemed to be highly specific for the atherosclerotic endothelium: macrophages and smooth muscle cells that were exposed to oxLDL expressed miR-92a only at a low level. The authors unequivocally showed in vivo evidence for the importance of atheromiR-92a by treating ldlr −/− mice with an antagomir against miR-92a. Treated ldlr −/− mice did not only show a reduction in plaque area but also developed plaques that contained less T cells and macrophages and contained more fibrosis, 4 a phenotype that is reminiscent of a stable human atherosclerotic plaque.The findings of Loyer et al 4 are not unexpected. MiR-92a, which is part of the miR-17-92 cluster, has been proposed to be a therapeutic target for cardiovascular disease before. Several articles have found the miR-17-92 cluster to be correlated with regions of low shear stress. MiR-92a was found to be upregulated in endothelial cells by oscillatory flow. 5 In vivo, miR-92a was ...

show abstract

Inhibition of MicroRNA-92a Protects Against Ischemia/Reperfusion Injury in a Large-Animal Model

Cited by 290 publications

References 23 publications

RNA Therapeutics for Treatment of Cardiovascular Diseases

RNA Therapeutics for Treatment of Cardiovascular Diseases

MiR-92a – a key player in cardiovascular remodeling

MiR-92a

Contact Info

Product

Resources

About