Patients with diabetes have mortality from cardiovascular disease that is over twice that observed in the general population, resulting in atherosclerotic plaque formation. The diabetic plaque is characterised by abnormalities in both endothelial and vascular smooth muscle cell function. Within the atherosclerotic cytokine network, tumor necrosis factor-alpha (TNF-alpha) and platelet-derived growth factor (PDGF) are implicated as key molecular drivers. Lipoxins are naturally-occurring, small molecule lipid mediators with the potential to treat multiple inflammatory diseases. Here we investigated the potency of ω-6 arachidonic acid derived lipoxin A4 (LXA4) in attenuating endothelial and vascular smooth muscle cell dysfunction observed in atherosclerosis.

Primary mouse aortic endothelial cells and vascular smooth muscle cells were stimulated with PDGF (5ng/ml) or TNF-alpha (1ng/ml) with or without lipoxin A4 (0.1nM), and markers of inflammation and fibrosis were assessed. Lipoxin A4 significantly attenuated both PDGF and TNF-alpha signalling in smooth muscle and endothelial cells through inhibition of expression of PDGF-receptor (PDGFRβ1), TNF-receptor (TNFR1), vascular cell adhesion molecule-1 (VCAM), monocyte chemoattractant protein 1 (MCP1) and pro-inflammatory interleukin 6 (IL-6). Lipoxin A4 suppressed PDGF-mediated migration and proliferation, and TNF-alpha mediated NF-κB activity in smooth muscle cells. Furthermore, lipoxin A4 significantly attenuated TNF-alpha mediated monocyte adhesion to aortic endothelial cells.

Taken together, our data suggests that lipoxin A4 may be used as a novel therapeutic in diabetes-associated atherosclerosis, through inhibition of PDGF and TNF-alpha signalling pathways in vascular cells.