RT Journal Article
SR Electronic
T1 Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 2657
OP 2667
DO 10.2337/db17-1317
VO 67
IS 12
A1 Brennan, Eoin P.
A1 Mohan, Muthukumar
A1 McClelland, Aaron
A1 de Gaetano, Monica
A1 Tikellis, Christos
A1 Marai, Mariam
A1 Crean, Daniel
A1 Dai, Aozhi
A1 Beuscart, Ophelie
A1 Derouiche, Sinda
A1 Gray, Stephen P.
A1 Pickering, Raelene
A1 Tan, Sih Min
A1 Godson-Treacy, Molly
A1 Sheehan, Stephen
A1 Dowdall, Joseph F.
A1 Barry, Mary
A1 Belton, Orina
A1 Ali-Shah, Syed Tasadaque
A1 Guiry, Patrick J.
A1 Jandeleit-Dahm, Karin
A1 Cooper, Mark E.
A1 Godson, Catherine
A1 Kantharidis, Phillip
YR 2018
UL http://diabetes.diabetesjournals.org/content/67/12/2657.abstract
AB 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.