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- Title
Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis.
- Authors
Brennan, Eoin P.; Mohan, Muthukumar; McClelland, Aaron; de Gaetano, Monica; Tikellis, Christos; Marai, Mariam; Crean, Daniel; Dai, Aozhi; Beuscart, Ophelie; Derouiche, Sinda; Gray, Stephen P.; Pickering, Raelene; Tan, Sih Min; Godson-Treacy, Molly; Sheehan, Stephen; Dowdall, Joseph F.; Barry, Mary; Belton, Orina; Ali-Shah, Syed Tasadaque; Guiry, Patrick J.
- 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.
- Subjects
LIPOXINS; ATHEROSCLEROSIS; DIABETES; INFLAMMATION; VASCULAR smooth muscle; ENDOTHELIAL cells; DIABETES complications; ANIMAL experimentation; ANTIGENS; AORTA; COMPARATIVE studies; CYTOKINES; INFLAMMATORY mediators; INTERLEUKIN-1; INTERLEUKINS; RESEARCH methodology; MEDICAL cooperation; MICE; NONSTEROIDAL anti-inflammatory agents; RESEARCH; EICOSANOIDS; EVALUATION research; PHARMACODYNAMICS; THERAPEUTICS
- Publication
Diabetes, 2018, Vol 67, Issue 12, p2657
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db17-1317