MiR-92a – a key player in cardiovascular remodeling

Abstract

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...