Back to Search Start Over

Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis

Authors :
Eoin P. Brennan
Monica de Gaetano
Raelene Pickering
Sinda Derouiche
Bo Wang
Patrick J. Guiry
Muthukumar Mohan
Phillip Kantharidis
Catherine Godson
Stephen P. Gray
Karin Jandeleit-Dahm
Orina Belton
Mark E. Cooper
Ophelie Beuscart
Chris Tikellis
Mary Barry
Mariam Marai
Aaron McClelland
Syed Tasadaque Ali-Shah
Source :
Diabetes. 66:2266-2277
Publication Year :
2017
Publisher :
American Diabetes Association, 2017.

Abstract

The let-7 miRNA family plays a key role in modulating inflammatory responses. Vascular smooth muscle cell (SMC) proliferation and endothelial cell (EC) dysfunction are critical in the pathogenesis of atherosclerosis, including in the setting of diabetes. Here we report that let-7 levels are decreased in diabetic human carotid plaques and in a model of diabetes-associated atherosclerosis, the diabetic ApoE−/− mouse. In vitro platelet-derived growth factor (PDGF)– and tumor necrosis factor-α (TNF-α)–induced vascular SMC and EC activation was associated with reduced let-7 miRNA expression via Lin28b, a negative regulator of let-7 biogenesis. Ectopic overexpression of let-7 in SMCs inhibited inflammatory responses including proliferation, migration, monocyte adhesion, and nuclear factor-κB activation. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in SMCs using an endogenous anti-inflammatory lipid (lipoxin A4), ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease.

Details

ISSN :
1939327X and 00121797
Volume :
66
Database :
OpenAIRE
Journal :
Diabetes
Accession number :
edsair.doi.dedup.....a65ae42d2f92878d2f29d86ccc6b681b
Full Text :
https://doi.org/10.2337/db16-1405