期刊
DIABETES
卷 67, 期 12, 页码 2657-2667出版社
AMER DIABETES ASSOC
DOI: 10.2337/db17-1317
关键词
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资金
- ELEVATE Irish Research Council/H2020 Marie Sklodowska-Curie Actions Fellowship
- NHMRC, the joint JDRF/NHMRC CRE program
- Victorian Government's Operational Infrastructure Support (OIS) Program
- Science Foundation Ireland, Health Research Board
- JDRF Australia [15/IA/3152, 15/US/B3130, 11/PI/1206]
- Science Foundation Ireland (SFI) [11/PI/1206] Funding Source: Science Foundation Ireland (SFI)
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 (LXA(4)). Here, we explored the therapeutic potential of LXA(4) and a synthetic LX analog (Benzo-LXA(4)) 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-1, was significantly attenuated by both LXA(4) and Benzo-LXA(4) 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 + LXA(4)]; 13.19 +/- 1.97% [diabetic + Benzo-LXA(4)]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor- and interleukin-1. 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.
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