BACKGROUND AND PURPOSE Lipocalin‐2 is a pro‐inflammatory adipokine up‐regulated in obese human subjects and animal models. Its circulating levels are positively correlated with the unfavourable lipid profiles, elevated blood pressure and insulin resistance index. Augmented lipocalin‐2 has been found in patients with cardiovascular abnormalities.The present study was designed to investigate the role of lipocalin‐2 in regulating endothelial function and vascular reactivity.

EXPERIMENTAL APPROACH Wild‐type and lipocalin‐2 knockout (Lcn2‐KO) mice were fed with either a standard chow or a high‐fat diet. Blood pressures and endothelium‐dependent relaxations/contractions were monitored at 2 week intervals.

RESULTS Systolic blood pressure was elevated by high‐fat diet in wild‐type mice but not in Lcn2‐KO mice. Endothelial dysfunction, reflected by the impaired endothelium‐dependent relaxations to insulin and augmented endothelium‐dependent contractions to ACh, was induced by high‐fat diet in wild‐type mice. In contrast, Lcn2‐KO mice were largely protected from the deterioration of endothelial function caused by dietary challenges. The eNOS dimer/monomer ratio, NO bioavailability, basal and insulin‐stimulated PKB/eNOS phosphorylation responses were higher in aortae of Lcn2‐KO mice. Administration of lipocalin‐2 attenuated endothelium‐dependent relaxations to insulin and promoted endothelium‐dependent contractions to ACh. It induced eNOS uncoupling and elevated COX expression in the arteries. Treatment with sulphaphenazole, a selective inhibitor of cytochrome P450 2C9, improved endothelial function in wild‐type mice and blocked the effects of lipocalin‐2 on both endothelium‐dependent relaxations to insulin and endothelium‐dependent contractions to ACh, as well as eNOS uncoupling.

CONCLUSIONS Lipocalin‐2, by modulating cytochrome P450 2C9 activity, is critically involved in diet‐induced endothelial dysfunction.