Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury

Daniel, Jan‐Marcus; Penzkofer, Daniela; Teske, Rebecca; Dutzmann, Jochen; Koch, Alexander; Bielenberg, Wiebke; Bonauer, Angelika; Boon, Reinier A.; Fischer, Ariane; Bauersachs, Johann; Rooij, Eva van; Dimmeler, Stefanie; Sedding, Daniel

doi:10.1093/cvr/cvu162

Cited by 131 publications

(104 citation statements)

References 28 publications

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“…Furthermore, we found a reduced number of CD68 + monocytes/ macrophages accumulating in the lesions as well as a reduced number of proliferating Ki67 + SMCs within the vessel wall, and an impairment of neointima lesion development. As expected, the expression of the pro-angiogenic miR-92a target genes Sirt1 and Itga5 was strongly increased at 2 weeks after wire-induced injury [11] . Itga5 interacts with fibronectin, which represents the major component of the early extracellular matrix, and its expression has been shown to be an important prerequisite for vascular regeneration [12] .…”

Section: Research Highlightsupporting

confidence: 82%

“…Neither ECs nor SMCs showed changed apoptotic rates following sole overexpression of miR-92a [11] . We then abrogated miR-92a expression following vascular injury by the use of two different strategies.…”

Section: Research Highlightmentioning

confidence: 88%

“…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 overexpression of miR-92a in EC in vitro, we observed a significantly reduced proliferation and migration in ECs but not in SMCs, suggesting that the functional RESEARCH HIGHLIGHT…”

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confidence: 99%

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MiR-92a – a key player in cardiovascular remodeling

Dutzmann¹,

Daniel

Bauersachs³

et al. 2015

RNA Dis

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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...

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Section: Research Highlightsupporting

confidence: 82%

Section: Research Highlightmentioning

confidence: 88%

mentioning

confidence: 99%

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MiR-92a – a key player in cardiovascular remodeling

Dutzmann¹,

Daniel

Bauersachs³

et al. 2015

RNA Dis

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“…Among the miRNAs whose expression is regulated by developmental IGF-1 deficiency, upregulation of miR-125a-5p has been linked to impaired angiogenesis and endothelial dysfunction (Che et al 2014), endothelial apoptosis (Svensson et al 2014), and dysregulation of endothelial tight junctions (Reijerkerk et al 2013). miR-92a promotes atherosclerosis, endothelial dysfunction (Loyer et al 2014), and neointima formation (Daniel et al 2014). miR-126 is a biomarker of clinical atherosclerosis (Kim et al 2015).…”

Section: Discussionmentioning

confidence: 99%

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

Tarantini

Giles

Wren

et al. 2016

AGE

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Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 f/f mice crossed with mice expressing albumindriven Cre recombinase). This model exhibits lowcirculating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from AGE (2016) 38:239-258

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“…The inhibition of miR-92a expression prevents endothelial activation and dysfunction in vivo and promotes the anti-inflammatory phenotype 113) . Another study showed that miR-92a inhibition improves re-endothelialization, which enhances functional recovery following vascular injury in vivo 114) . The described findings about miR-92a in atherosclerosis make it a potential therapeutic target in vascular pathology.…”

Section: Conflict Of Interest Statementmentioning

confidence: 99%

CXCL16 in Vascular Pathology Research: from Macro Effects to microRNAs

Jovanović

Živković

Djurić

et al. 2015

J Atheroscler Thromb

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Chemokines and their receptors have become significant factors in atherosclerosis research. CXCL16 is a multifunctional agent located on a separate locus to all other known chemokines and binds only to its "unique" receptor named CXCR6. As a scavenger receptor, adhesion molecule, and chemokine, it quickly became an interesting target in atherosclerosis research as all its functions have a role in vascular pathology. The investigation of the role of CXCL16 in atherosclerosis, although shown in in vitro studies, animal knockout models, and CXCL16 gene polymorphisms, haplotypes, and circulating levels, still shows puzzling results. Genetic and epigenetic studies have just scratched the surface of research necessary for a better assessment of the significance and perspective of this marker in plaque development and progression. In this review, we will summarize current knowledge about CXCL16 in atherosclerosis. Additionally, we will point out the importance of bioinformatics tools for the detection of potentially new CXCL16 regulatory networks through microRNA activity. This review aims to provide a better understanding of the underlying mechanisms, define more specific biomarkers, and discover new therapeutic targets.

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Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury

Cited by 131 publications

References 28 publications

MiR-92a – a key player in cardiovascular remodeling

MiR-92a – a key player in cardiovascular remodeling

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

CXCL16 in Vascular Pathology Research: from Macro Effects to microRNAs

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