The small, highly conserved peptide urotensin II (UII) is up-regulated in atherosclerosis, however its effects in upon the in the diabetic setting have never been assessed. The aims of this study were to examine UII’s effects in vitro and in vivo in endothelial cells and diabetes-associated atherosclerosis, respectively.

 Apolipoprotein E KO mice (+/- streptozotocin-induced diabetes) with or with-out SB-657510 treatment (30mg/kg/day; n=20/group) were followed for 20 weeks. Mouse aortas were assessed for plaque area before being embedded in paraffin for immunohistochemistry. Furthermore, carotid endarectomies from diabetic and non-diabetic patients were embedded for immunohistochemistry.

Endothelial cells were grown in high (25mM) and low (5mM) glucose media with and without UII (10^-8M) and/or the urotensin II receptor antagonist SB-657510 (10^-10M). HAECs were processed for gene expression whilst monocyte adhesion with THP-1 cells was assessed in HUVECs.

 Staining for both UII and MCP-1 were significantly attenuated in diabetic treated animals. UII staining was significantly increased in carotid endarectomies from diabetic patients compared to non-diabetic patients, as was staining for MCP-1.

In high (but not low) glucose media UII significantly increase MCP-1 gene expression (HAECs) and increase monocyte adhesion (HUVECs). This was attenuated by UII receptor antagonism. UII receptor antagonism also significantly attenuated diabetes-associated atherosclerosis in mice.

 In conclusion this study is the first report that UII is increased in diabetes-associated atherosclerosis in both human and animal tissue with UII also having more pro-atherogenic effects in the diabetic milieu in vitro. Thus UII may present a potential novel therapeutic target in the treatment of diabetes-associated atherosclerosis.