Abstract
Peripheral artery disease (PAD) is a vascular disease involving diffuse atherosclerosis, and is associated with increased cardiovascular mortality and morbidity. Critical limb ischemia (CLI) is the most severe complication of PAD. In addition to medical and interventional treatment, therapeutic angiogenesis is a novel therapy for PAD. Circulating microRNAs (miRNAs) are considered key regulators of gene expression, but their role in ischemic-induced angiogenesis is poorly-characterized. There is currently a limited understanding of the specific miRNAs associated with PAD. To determine the regulation of miRNAs, we obtained miRNA profiles using RNA isolated from patients with PAD and a control group. The effects of specific miRNAs on angiogenesis were evaluated by assessing the in vitro angiogenic function of endothelial progenitor cells (EPCs), performing an in vivo angiogenesis assay, and employing a mouse hindlimb ischemic model. Our results demonstrated that circulating miR-548j-5p was significantly reduced in patients with PAD as compared with the controls. miR-548j-5p promoted EPC angiogenesis by enhancing migration and tube formation. The endothelial nitric oxide synthase (NOS) and stromal cell-derived factor (SDF)-1 signaling pathways appeared to be potential targets of miR-548j-5p. Furthermore, the results of a directed in vivo angiogenesis assay of EPCs and a hindlimb ischemia mouse model demonstrated that miR-548j-5p enhanced the capillary density and blood flow recovery in hindlimb ischemia. In conclusion, our data indicated that up-regulation of miR-548j-5p promotes angiogenesis in ischemic tissue and may represent a novel therapeutic approach for PAD.
Highlights
Peripheral artery disease (PAD) is a vascular disease involving diffuse atherosclerosis, and is associated with increased cardiovascular mortality and morbidity
MiR548j-5p mimic transfection of endothelial progenitor cells (EPCs) upregulated the stromal cell-derived factor (SDF)-1 expression. These results suggested that miR-548j-5p could regulate EPC function via the eNOS and SDF-1 signaling pathways
Using an in vivo angiogenesis assay, this study demonstrated that transfection of EPCs with miR-548j-5p could enhance the activities of eNOS and SDF-1 and improve EPC functions such as migration and tube formation, whereas miR-548j-5p antagomir transfection impaired the angiogenic activities of EPCs
Summary
Peripheral artery disease (PAD) is a vascular disease involving diffuse atherosclerosis, and is associated with increased cardiovascular mortality and morbidity. Our data indicated that up-regulation of miR-548j-5p promotes angiogenesis in ischemic tissue and may represent a novel therapeutic approach for PAD. Abbreviations ABI Ankle brachial index CLI Critical limb ischemia eNOS Endothelial nitric oxide synthase EPC Endothelial progenitor cell FGF1 Fibroblast growth factor-1 miRNA MicroRNA NO Nitric oxide PAD Peripheral artery disease SDF-1 Stromal cell-derived factor-1 SEM Standard error of the mean VEGF Vascular endothelial growth factor. Previous studies have shown that specific miRNA expression profiles in patients with PAD may serve as prognostic predictors[7]. There is some evidence to indicate that endothelial progenitor cells (EPCs) are involved in angiogenesis in patients with postmyocardial infarction[10] and limb ischemia[11]. In order to identify the mechanisms underlying regulation of the progress of PAD by miRNAs, additional studies are required to validate miRNAs with the potential for use in the treatment of this class of diseases
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