Besnier, Marie, Shantikumar, Saran, Anwar, Maryam, Dixit, Parul, Chamorro-Jorganes, Aranzazu, Sweaad, Walid, Sala-Newby, Graciela, Madeddu, Paolo, Thomas, Anita C., Howard, Lynsey, Mushtaq, Sobia, Petretto, Enrico, Caporali, Andrea and Emanueli, Costanza (2019) MiR-15a/-16 inhibit angiogenesis by targeting Tie2 coding sequence : therapeutic potential of a miR-15a/16 decoy system in limb ischemia. Molecular Therapy - Nucleic Acids, 17 . pp. 49-62. doi:10.1016/j.omtn.2019.05.002 ISSN 2162-2531.

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Abstract

MicroRNA-15a (miR-15a) and miR-16, which are transcribed from the miR-15a/miR-16-1 cluster, inhibit post-ischemic angiogenesis. MicroRNA (miRNA) binding to mRNA coding sequences (CDSs) is a newly emerging mechanism of gene expression regulation. We aimed to (1) identify new mediators of the anti-angiogenic action of miR-15a and -16, (2) develop an adenovirus (Ad)-based miR-15a/16 decoy system carrying a luciferase reporter (Luc) to both sense and inhibit miR-15a/16 activity, and (3) investigate Ad.Luc-Decoy-15a/16 therapeutic potential in a mouse limb ischemia (LI) model. LI increased miR-15a and -16 expression in mouse muscular endothelial cells (ECs). The miRNAs also increased in cultured human umbilical vein ECs (HUVECs) exposed to serum starvation, but not hypoxia. Using bioinformatic tools and luciferase activity assays, we characterized miR-15a and -16 binding to Tie2 CDS. In HUVECs, miR-15a or -16 overexpression reduced Tie2 at the protein, but not the mRNA, level. Conversely, miR-15a or -16 inhibition improved angiogenesis in a Tie2-dependent manner. Local Ad.Luc-Decoy-15a/16 delivery increased Tie2 levels in ischemic skeletal muscle and improved post-LI angiogenesis and perfusion recovery, with reduced toe necrosis. Bioluminescent imaging (in vivo imaging system [IVIS]) provided evidence that the Ad.Luc-Decoy-15a/16 system responds to miR-15a/16 increases. In conclusion, we have provided novel mechanistic evidence of the therapeutic potential of local miR-15a/16 inhibition in LI.

Item Type:	Journal Article
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Population, Evidence & Technologies (PET) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Journal or Publication Title:	Molecular Therapy - Nucleic Acids
Publisher:	Elsevier Inc.
ISSN:	2162-2531
Official Date:	6 September 2019
Dates:	Date Event 6 September 2019 Published 16 May 2019 Available 5 May 2019 Accepted
Volume:	17
Page Range:	pp. 49-62
DOI:	10.1016/j.omtn.2019.05.002
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	3 June 2019
Date of first compliant Open Access:	3 June 2019
Funder:	(RG/15/5/31446), Chair in Cardiovascular Science (CH/15/1/31199) and a British H
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