miR-19a-3p Containing Exosomes Improve Cardiac Function in Ischemic Myocardium

J. Holfeld; L. Pölzl; M. Graber; J. Hirsch; D. Lobenwein; J. Zipperle; M. Blumer; E. Kirchmair; R. Kirchmair; P. Paulus; S. Davidson; M. Grimm; C. Tepeköylü

doi:10.1055/s-0038-1627831

The Thoracic and Cardiovascular Surgeon, Table of Contents

Thorac Cardiovasc Surg 2018; 66(S 01): S1-S110
DOI: 10.1055/s-0038-1627831

Oral Presentations

Sunday, February 18, 2018

DGTHG: Basic Science: Myocardial Protection

Georg Thieme Verlag KG Stuttgart · New York

miR-19a-3p Containing Exosomes Improve Cardiac Function in Ischemic Myocardium

Authors

J. Holfeld

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
L. Pölzl

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
M. Graber

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
J. Hirsch

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
D. Lobenwein

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
J. Zipperle

²AUVA Research Centre Vienna, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Innsbruck, Austria
M. Blumer

³Department of Anatomy, Medical University of Innsbruck, Innsbruck, Austria
E. Kirchmair

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
R. Kirchmair

⁴Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria
P. Paulus

⁵Department of Anesthesiology, Medical University of Linz, Linz, Austria
S. Davidson

⁶Hatter Cardiovascular Institute, University College London, London, United Kingdom
M. Grimm

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria
C. Tepeköylü

¹Department of Cardiac Surgery, Medical University of Innsbruck, Innsbruck, Austria

Abstract

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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.