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Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction

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Abstract

MicroRNA-144 is a cytoprotective miRNA. Our previous study showed that miR-144 provides potent acute cardioprotection in an ischemia/reperfusion injury model. This study was performed to further assess whether miR-144 improves post-MI remodeling in a non-reperfused myocardial infarction (MI) model. C57BL/6 mice were subjected to MI by permanent left anterior descending artery (LAD) ligation. miR-144 was delivered by intravenous injections of 8 mg/kg, 16 mg/kg, or 32 mg/kg at day 0, day 1, day 3, and then a similar dose given once every 3 days, until day 28 after MI. Cardiac function was evaluated using echocardiography. At the end of the study, heart function was also evaluated using a pressure volume catheter. The percentage of the length of the infarct scar on the left ventricle (LV) circumferential length was calculated for heart each section. The miR-144 KO mice showed a worse heart failure phenotype with ventricular dilation and impaired contractility after LAD ligation. Ischemia decreased miR-144 levels, and the miR-144 level was restored to baseline by administration of intravenous miR-144. Cy3-labeled miR-144 was localized to the infarct and border zone, and was taken up by cardiomyocytes and macrophages. In miR-144-treated groups, at 28 days MI size was significantly reduced, and cardiac function was improved [LV fractional shortening, end-systolic volume (µL), end-diastolic volume (µL), ejection fraction (%), dP/dt max (mmHg/s), dP/dt min (mmHg/s), Tau (ms)], compared with controls (p < 0.01). This beneficial effect was associated with reduced border zone fibrosis, inflammation and apoptosis, these effects were associated with significant changes in autophagy signaling. Intravenous miR-144 has potent effects on post-MI remodeling. These findings suggest that miR-144 has potential as a therapeutic agent after MI.

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Acknowledgements

This study was supported by a grant from the Canadian Institute of Health Research, Grant number: MOP-133469 (A. Redington).

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Authors and Affiliations

  1. Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, Toronto, ON, Canada

    Jing Li, Helena Zhang & Andrew N. Redington

  2. University Health Network, Toronto, ON, Canada

    Sean XiaoXiao Cai

  3. McMaster University, Hamilton, ON, Canada

    Daniel Friedberg

  4. Department of Pediatrics, Heart Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229-3026, USA

    Quan He, Fangfei Wang & Andrew N. Redington

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  1. Jing Li
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Li, J., Cai, S.X., He, Q. et al. Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction. Basic Res Cardiol 113, 36 (2018). https://doi.org/10.1007/s00395-018-0694-x

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