title: Lipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: role of cytochrome P450 2C inhibition.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong.
authors: Jacky T C
authors: JT
authors: Liu
authors: Erfei
authors: E
authors: Song
authors: Aimin
authors: A
authors: Xu
authors: Thorsten
authors: T
authors: Berger
authors: Tak W
authors: TW
authors: Mak
authors: Hung-Fat
authors: HF
authors: Tse
authors: Ivy K M
authors: IK
authors: Law
authors: Bosheng
authors: B
authors: Huang
authors: Yan
authors: Y
authors: Liang
authors: Paul M
authors: PM
authors: Vanhoutte
authors: Yu
authors: Y
authors: Wang
mesh_terms: D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D001794:Blood Pressure; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D066298:In Vitro Techniques; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D000071068:Lipocalin-2; D054834:Lipocalins; D009566:Nitrates; D009573:Nitrites; D015513:Oncogene Proteins; C400322:cytochrome P-450 CYP2C subfamily; D013481:Superoxides; C071332:Lcn2 protein, mouse; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases; D019255:NADPH Oxidases