Mir-187 regulation in primary cardiomyocyte and murine model of experimental sepsis-induced myocardial dysfunction
CCCF ePoster library. Ektesabi A. 11/11/19; 283410; EP33
Amin Ektesabi
Amin Ektesabi
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Topic: Basic or Translational Science

Ektesabi, Amin M.1,2,7; Tsoporis, Jim2; Varkouhi, Amir K.2; Teixeira, Ana Paula M.2; Mori, Keisuke 2,3; Walsh, Chris3; Mei, Shirley4; Stewart, Duncan J.4;  Conrad Liles W.5; Hu, Pingzhao6; Parker, Thomas2; dos Santos, Claudia C.1,2,3,7


1Institude of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, CA. 2Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, CA. 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, CA. 4Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, ON, CA. 5Department of Medicine, University of Washington, Seattle, WA, USA. 6Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MA, CA.7Institude of medical sciences, University of Toronto, Toronto, ON, CA.

Background: Multiple microRNAs (miRs) are dysregulated during myocardial dysfunction in sepsis. Systemic administration of mesenchymal stromal/stem cells (MSCs) mitigates sepsis induced myocardial dysfunction and alters the expression of both miRs and their target mRNAs in the septic heart. In an experimental model, we have identified miR-187 as a putative host-derived MSC-regulated miR. Here we investigate, in vitro and in vivo, the in-silico hypothesis that miR-187 plays a critical role in the pathogenesis and therapeutics of sepsis-induced myocardial dysfunction.

Methods: Male wild-type mice (C57Bl/6J, 10 - 14 weeks) were randomized to sham or cecum ligation and puncture (CLP) and further randomized to receive MSCs (2 x 105 cells, tail vein) or placebo, 6 hours post surgery. Mice were sacrificed at 28hrs and hearts collected for protein, histology and RNA analysis. Transthoracic echocardiograms were performed at 48 hrs in a separate group of mice. Primary cardiomyocytes were harvested from 1-2 days old neonates and exposed to endotoxin (lipopolysaccharide, 2µg/mL) or IL-10 (10 ng/ml) ± MSCs (1x104 cells/ well). Cells were lysed, RNA isolated 24 hours post-treatment, and analyzed using qRT-PCR.

Results: MSC administration mitigated CLP-induced left ventricular dilatation and decreased ejection fraction. Quantitative real-time PCR confirmed differential expression of pre-identified in-silico targets in-vivo and IL-10, an anti-inflammatory cytokine, in murine septic hearts treated with MSCs. In vitro, miR-187 expression levels were significantly lower in primary neonatal cardiomyocytes, exposed to endotoxin while the expressions of its putative target genes were increased. Similarly, IL-10 expression was decreased in LPS treated cells; this was mitigated by MSC administration.

Conclusion: MSC administration results in the regulation of host-derived miRNAs involved in protecting cardiomyocytes from sepsis-induced inflammation.

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