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Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis

Authors :
Phillip Kantharidis
Aaron McClelland
Syed Tasadaque Ali-Shah
Christos Tikellis
Orina Belton
Mark E. Cooper
Sih Min Tan
Eoin P. Brennan
Ophelie Beuscart
Karin Jandeleit-Dahm
Mary Barry
Monica de Gaetano
Raelene Pickering
Sinda Derouiche
Catherine Godson
Stephen P. Gray
Stephen Sheehan
Molly Godson-Treacy
Patrick J. Guiry
Joseph Dowdall
Daniel Crean
Mariam Marai
Muthukumar Mohan
Aozhi Dai
Source :
Diabetes. 67(12)
Publication Year :
2017

Abstract

Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA4). Here, we explored the therapeutic potential of LXA4 and a synthetic LX analog (Benzo-LXA4) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE−/− mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1, mcp-1, il-6, and il-1β, was significantly attenuated by both LXA4 and Benzo-LXA4 in diabetic ApoE−/− mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 ± 2.01% [diabetic]; 12.67 ± 1.68% [diabetic + LXA4]; 13.19 ± 1.97% [diabetic + Benzo-LXA4]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor–stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.

Details

ISSN :
1939327X
Volume :
67
Issue :
12
Database :
OpenAIRE
Journal :
Diabetes
Accession number :
edsair.doi.dedup.....e6d6d4eb8ab5999148442c9f0554b72f