Lipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: role of cytochrome P450 2C inhibition

Br J Pharmacol. 2012 Jan;165(2):520-31. doi: 10.1111/j.1476-5381.2011.01587.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / deficiency
  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / physiology*
  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / physiopathology*
  • Blood Pressure
  • Carotid Arteries / drug effects
  • Carotid Arteries / metabolism
  • Carotid Arteries / physiopathology*
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Diet, High-Fat
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology*
  • In Vitro Techniques
  • Lipocalin-2
  • Lipocalins / genetics
  • Lipocalins / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidases / metabolism
  • Nitrates / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrites / metabolism
  • Obesity / metabolism
  • Obesity / physiopathology*
  • Oncogene Proteins / deficiency
  • Oncogene Proteins / genetics
  • Oncogene Proteins / physiology*
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Superoxides / metabolism


  • Acute-Phase Proteins
  • Cytochrome P-450 Enzyme Inhibitors
  • Lipocalin-2
  • Lipocalins
  • Nitrates
  • Nitrites
  • Oncogene Proteins
  • cytochrome P-450 CYP2C subfamily
  • Superoxides
  • Lcn2 protein, mouse
  • Nitric Oxide
  • Cytochrome P-450 Enzyme System
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Prostaglandin-Endoperoxide Synthases
  • NADPH Oxidases