Protective effect of let-7 miRNA family in regulating inflammation in diabetes-associated atherosclerosis

Eoin P Brennan, Bo Wang, Aaron McClelland, Muthukumar Mohan, Mariam Marai, Ophelie Beuscart, Sinda Derouiche, Stephen Gray, Raelene Pickering, Chris Tikellis, Monica De Gaetano, Mary Barry, Orina Belton, Syed Tasadaque Ali-Shah, Patrick Guiry, Karin A.M. Jandeleit-Dahm, Mark E. Cooper, Catherine Godson, Phillip Kantharidis

Research output: Contribution to journalArticleResearchpeer-review

54 Citations (Scopus)

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 diabetesassociated atherosclerosis, the diabetic ApoE2/2 mouse. In vitro platelet-derived growth factor (PDGF)-and tumor necrosis factor-a (TNF-a)-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-kB 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.

Original languageEnglish
Pages (from-to)2266-2277
Number of pages12
JournalDiabetes
Volume66
Issue number8
DOIs
Publication statusPublished - 1 Aug 2017

Cite this

Brennan, E. P., Wang, B., McClelland, A., Mohan, M., Marai, M., Beuscart, O., Derouiche, S., Gray, S., Pickering, R., Tikellis, C., De Gaetano, M., Barry, M., Belton, O., Ali-Shah, S. T., Guiry, P., Jandeleit-Dahm, K. A. M., Cooper, M. E., Godson, C., & Kantharidis, P. (2017). Protective effect of let-7 miRNA family in regulating inflammation in diabetes-associated atherosclerosis. Diabetes, 66(8), 2266-2277. https://doi.org/10.2337/db16-1405