Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis

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 (LXA). Here, we explored the therapeutic potential of LXA and a synthetic LX analog (Benzo-LXA) 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 ,, , and, was significantly attenuated by both LXA and Benzo-LXA 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]; 13.19 ± 1.97% [diabetic + Benzo-LXA]). 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.

The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice

“…Earlier studies have reported that activation of FPR results in anti-inflammatory responses in endothelial cells [10,40]. In the present study, diabetes caused the upregulation of the expression of the pro-inflammatory cytokine, IL1β, contributing to a selective impairment of endothelium-dependent relaxation, indicating endothelial dysfunction as previously described [41][42][43][44][45][46].…”

Lipoxin A4 Inhibits NLRP3 Inflammasome Activation in Rats With Non-compressive Disc Herniation Through the JNK1/Beclin-1/PI3KC3 Pathway

“…LXs are important "brake signals" for relieving and inhibiting neutrophil recruitment, and stimulate autophagy in monocytes and macrophages (Hughes et al, 2017). They can also regulate cytokine secretion and expression, which greatly contributes to the pathophysiology of chronic pain (Brennan et al, 2018).…”

The diets of sows with fish oil might decrease the oxidative stress and inflammatory response in sows, but increase the susceptibility to inflammatory response in their offspring

“…NF-κB DNA binding activity further increased at 24 and 48 h after in ammatory stimulation in the presence of IκBα protein [34]. Myeloid cells represent a major target for LXA4 and re ect the attenuation of NF-κB activity [35][36][37]. Therefore, n-6 PUFA participates in the resolution of in ammation [38].…”