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Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis
- 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.
- Subjects :
- 0301 basic medicine
Vascular smooth muscle
Endocrinology, Diabetes and Metabolism
Interleukin-1beta
Vascular Cell Adhesion Molecule-1
Inflammation
030204 cardiovascular system & hematology
Pharmacology
Proinflammatory cytokine
Diabetes Mellitus, Experimental
03 medical and health sciences
Mice
0302 clinical medicine
Diabetes mellitus
Internal Medicine
Medicine
Animals
Humans
Aorta
Chemokine CCL2
Cell growth
business.industry
Interleukin-6
Anti-Inflammatory Agents, Non-Steroidal
medicine.disease
Atherosclerosis
Endothelial stem cell
Lipoxins
030104 developmental biology
Cytokines
Tumor necrosis factor alpha
medicine.symptom
business
Ex vivo
Subjects
Details
- ISSN :
- 1939327X
- Volume :
- 67
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....e6d6d4eb8ab5999148442c9f0554b72f