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Single dose of synthetic microRNA-199a or microRNA-149 mimic does not improve cardiac function in a murine model of myocardial infarction

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Abstract

Intramyocardial injection of synthetic microRNAs (miRs) has recently been reported to be beneficial after myocardial infarction (MI). We conducted a randomized blinded study to evaluate the efficacy and reproducibility of this strategy in a mouse model of reperfused MI using rigorous methodology. Mice undergoing a 60-min coronary occlusion followed by reperfusion were randomly assigned to control miR, hsa-miR-199a-3p, hsa-miR-149-3p, or hsa-miR-149-5p mimic treatment. Intramyocardial injections of miRs were performed in the border zone right after reperfusion. At 8 weeks after MI, there were no significant differences in ejection fraction (EF) among groups (EF = 27.1 ± 0.4% in control group [n = 6] and 25.9 ± 0.5%, 26.0 ± 0.8%, and 26.6 ± 0.6% in hsa-miR-199a-3p, hsa-miR-149-3p, or hsa-miR-149-5p groups, respectively [n = 9 each]). Net change (delta) in EF at 8 weeks compared with day 3 after MI was − 4.1% in control and − 3.2%, − 2.4%, and − 0.4% in the miR-treated groups (P = NS). Assessment of cardiac function by hemodynamic studies (a method independent of echocardiography) confirmed that there was no difference in left ventricular systolic or diastolic function among groups. Consistent with the functional data, histological analysis showed no difference in scar size, cardiomyocyte area, capillary density, collagen content, or apoptosis among groups. In conclusion, this randomized, blinded study demonstrates that intramyocardial injection of a single dose of synthetic hsa-miR-199a-3p, hsa-miR-149-3p, or hsa-miR-149-5p mimic does not improve cardiac function or remodeling in a murine model of reperfused MI. The strategy of using synthetic miR mimics for cardiac repair after MI needs to be evaluated with rigorous preclinical studies before its potential clinical translation.

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Data availability

All data and material are available from the corresponding author on reasonable request.

Abbreviations

miR:

MicroRNA

MI:

Myocardial infarction

LCA:

Left coronary artery

I/R:

Ischemia/reperfusion

ECG:

Electrocardiography

BrdU:

5-Bromo-2′-deoxyuridine

LV:

Left ventricle

EDV:

End-diastolic volume

ESV:

End-systolic volume

SV:

Stroke volume

EF:

Ejection fraction

PV loop:

Pressure–volume loop

Ees:

End-systolic elastance

Tau:

Relaxation time constant

IZ:

Infarct zone

BZ:

Border zone

RZ:

Remote zone

EdU:

Ethynyl-29-deoxyuridine

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Acknowledgements

This work was supported in part by the National Institutes of Health grants P01 HL078825 (RB) and UM1 HL113530 (RB).

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Authors and Affiliations

  1. Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA

    Yibing Nong, Yiru Guo, Anna Gumpert, Qianhong Li, Alex Tomlin, Xiaoping Zhu & Roberto Bolli

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  1. Yibing Nong
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  2. Yiru Guo
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  3. Anna Gumpert
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Contributions

RB designed experiments, supervised study, and revised manuscript. YN performed experiments, analyzed data, and wrote manuscript. YG supervised findings. AG, QL, AT, and XZ performed experiments and analyzed data.

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Correspondence to Roberto Bolli.

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All animal procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the University of Louisville Institutional Animal Care and Use Committee (protocol number:14034).

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11010_2021_4227_MOESM2_ESM.tif

Supplementary file2 Gross measurements of body weight, lung weight, and LV mass. A. Body weight measured at each time point during the 8 wks of follow-up. B. Lung weight to body weight ratio at euthanasia and organs harvesting. C. LV mass measured after the heart was sectioned into three transverse slices. D. LV mass to body weight ratio. Data are mean ± SEM. (TIF 637 kb)

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Nong, Y., Guo, Y., Gumpert, A. et al. Single dose of synthetic microRNA-199a or microRNA-149 mimic does not improve cardiac function in a murine model of myocardial infarction. Mol Cell Biochem 476, 4093–4106 (2021). https://doi.org/10.1007/s11010-021-04227-w

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