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DOI: 10.1055/s-0038-1627831
miR-19a-3p Containing Exosomes Improve Cardiac Function in Ischemic Myocardium
Publication History
Publication Date:
22 January 2018 (online)
Objectives: Regeneration of ischemic myocardium for patients with ischemic heart disease represents a major challenge in the field of cardiovascular research. Exosomes were shown to exert regenerative effects in ischemic myocardium. We could show recently that mechanical stimulation of ischemic tissue via shock waves causes exosome release. We hypothesized that released exosomes improve cardiac function in ischemic hearts.
Methods: Human umbilical vein endothelial cells (HUVECs) underwent mechanical stimulation via shock waves to induce exosome release. Exosomes were isolated subsequently from the supernatant and characterized by transmission electron microscopy and nanoparticle tracking analysis. Functional in vitro assays were performed to analyze the angiogenic potential of released exosomes. Exosome content was evaluated via a miRNA sequencing array. Exosomes and miRNA were injected intramyocardially in SCID mice after left anterior descending (LAD) ligation (n = 10). Heart function was analyzed via transthoracic echocardiography. qPCR for angiogenic genes and immunofluorescence staining for vessels was performed. Myocardial scar was quantified via Masson Trichrome staining.
Results: Exosomes exhibited strong angiogenic potential in vitro and resulted in AKT and ERK activation. miRNA assay showed high exosomal miR 19a-3p content. miR 19a-3p induced capillary tube formation and endothelial proliferation. Anitmir-19a-3p antagonized exosome effects. Injection of released exosomes in a murine model of LAD ligation resulted in improved left ventricular function (EF in %: 13.45 ± 3.56 versus 27.87 ± 2.18, p = 0.041) and decreased fibrosis (%:59.77 ± 7.0 versus 33.83 ± 5.95, p = 0.025). Exosome treatment caused increased myocardial expression of VEGF and VEGFR2 resulting in increased numbers of capillaries and arterioles. Myocardial injection of miR 19a-3p in ischemic hearts lead to improvement of left ventricular function, induction of angiogenesis and decreased fibrosis.
Conclusion: Intramyocardial injection of SW exosomes in ischemic myocardium results in significantly improved cardiac function and myocardial regeneration. miR 19a-3p was identified as responsible exosomal cargo for the observed regenerative effects. 19a-3p containing exosomes could develop an innovative approach for the regeneration of ischemic myocardium.