File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

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

TitleLipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibition
Authors
Keywordsadipokine
CYP2C9
endothelial dysfunction
eNOS
lipocalin-2
obesity
Issue Date2012
PublisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
Citation
British Journal Of Pharmacology, 2012, v. 165 n. 2, p. 520-531 How to Cite?
Abstract
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. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Persistent Identifierhttp://hdl.handle.net/10722/135237
ISSN
2013 Impact Factor: 4.990
2013 SCImago Journal Rankings: 2.253
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong Kong
Hong Kong Research Grant CouncilHKU777908M
HKU777208M
HKU780410M
Collaborative Research FundHKU2/07C
4/HKU/10C
Funding Information:

This work was supported by the grants from Seeding Funds for Basic Research of the University of Hong Kong; Hong Kong Research Grant Council grants (HKU777908M, HKU777208M and HKU780410M) and Collaborative Research Fund (HKU2/07C and 4/HKU/10C).

References

 

Author Affiliations
  1. The University of Hong Kong
  2. Ontario Cancer Institute University of Toronto
DC FieldValueLanguage
dc.contributor.authorLiu, JTCen_HK
dc.contributor.authorSong, Een_HK
dc.contributor.authorXu, Aen_HK
dc.contributor.authorBerger, Ten_HK
dc.contributor.authorMak, TWen_HK
dc.contributor.authorTse, HFen_HK
dc.contributor.authorLaw, IKMen_HK
dc.contributor.authorHuang, Ben_HK
dc.contributor.authorLiang, Yen_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.contributor.authorWang, Yen_HK
dc.date.accessioned2011-07-27T01:30:26Z-
dc.date.available2011-07-27T01:30:26Z-
dc.date.issued2012en_HK
dc.identifier.citationBritish Journal Of Pharmacology, 2012, v. 165 n. 2, p. 520-531en_HK
dc.identifier.issn0007-1188en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135237-
dc.description.abstractBackground 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. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1en_HK
dc.relation.ispartofBritish Journal of Pharmacologyen_HK
dc.rightsBritish Journal of Pharmacology. Copyright © John Wiley & Sons Ltd.-
dc.subjectadipokineen_HK
dc.subjectCYP2C9en_HK
dc.subjectendothelial dysfunctionen_HK
dc.subjecteNOSen_HK
dc.subjectlipocalin-2en_HK
dc.subjectobesityen_HK
dc.subject.meshAorta, Thoracic - drug effects - metabolism - physiopathology-
dc.subject.meshEndothelium, Vascular - drug effects - physiopathology-
dc.subject.meshLipocalins - genetics - physiology-
dc.subject.meshObesity - metabolism - physiopathology-
dc.subject.meshOncogene Proteins - deficiency - genetics - physiology-
dc.titleLipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibitionen_HK
dc.typeArticleen_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.emailTse, HF: hftse@hkucc.hku.hken_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.emailWang, Y: yuwanghk@hku.hken_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.identifier.authorityWang, Y=rp00239en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1111/j.1476-5381.2011.01587.xen_HK
dc.identifier.pmid21740414en_HK
dc.identifier.pmcidPMC3268203-
dc.identifier.scopuseid_2-s2.0-83755172751en_HK
dc.identifier.hkuros187316en_US
dc.identifier.hkuros195686-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-83755172751&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume165en_HK
dc.identifier.issue2en_HK
dc.identifier.spage520en_HK
dc.identifier.epage531en_HK
dc.identifier.isiWOS:000298481200018-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridLiu, JTC=36081869500en_HK
dc.identifier.scopusauthoridSong, E=54785178800en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK
dc.identifier.scopusauthoridBerger, T=12242304800en_HK
dc.identifier.scopusauthoridMak, TW=35269407400en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.scopusauthoridLaw, IKM=34872613000en_HK
dc.identifier.scopusauthoridHuang, B=27169619500en_HK
dc.identifier.scopusauthoridLiang, Y=35305492300en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK
dc.identifier.scopusauthoridWang, Y=34973733700en_HK

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats