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Article: Lipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibition
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TitleLipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibition
 
AuthorsLiu, JTC1
Song, E1
Xu, A1
Berger, T2
Mak, TW2
Tse, HF1
Law, IKM1
Huang, B1
Liang, Y1
Vanhoutte, PM1
Wang, Y1
 
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
 
CitationBritish Journal Of Pharmacology, 2012, v. 165 n. 2, p. 520-531 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1476-5381.2011.01587.x
 
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.
 
ISSN0007-1188
2012 Impact Factor: 5.067
2012 SCImago Journal Rankings: 1.488
 
DOIhttp://dx.doi.org/10.1111/j.1476-5381.2011.01587.x
 
PubMed Central IDPMC3268203
 
ISI Accession Number IDWOS:000298481200018
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).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLiu, JTC
 
dc.contributor.authorSong, E
 
dc.contributor.authorXu, A
 
dc.contributor.authorBerger, T
 
dc.contributor.authorMak, TW
 
dc.contributor.authorTse, HF
 
dc.contributor.authorLaw, IKM
 
dc.contributor.authorHuang, B
 
dc.contributor.authorLiang, Y
 
dc.contributor.authorVanhoutte, PM
 
dc.contributor.authorWang, Y
 
dc.date.accessioned2011-07-27T01:30:26Z
 
dc.date.available2011-07-27T01:30:26Z
 
dc.date.issued2012
 
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.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationBritish Journal Of Pharmacology, 2012, v. 165 n. 2, p. 520-531 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1476-5381.2011.01587.x
 
dc.identifier.doihttp://dx.doi.org/10.1111/j.1476-5381.2011.01587.x
 
dc.identifier.epage531
 
dc.identifier.hkuros187316
 
dc.identifier.hkuros195686
 
dc.identifier.isiWOS:000298481200018
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).

 
dc.identifier.issn0007-1188
2012 Impact Factor: 5.067
2012 SCImago Journal Rankings: 1.488
 
dc.identifier.issue2
 
dc.identifier.pmcidPMC3268203
 
dc.identifier.pmid21740414
 
dc.identifier.scopuseid_2-s2.0-83755172751
 
dc.identifier.spage520
 
dc.identifier.urihttp://hdl.handle.net/10722/135237
 
dc.identifier.volume165
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/bw/journal.asp?ref=0007-1188&site=1
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofBritish Journal of Pharmacology
 
dc.relation.referencesReferences in Scopus
 
dc.rightsBritish Journal of Pharmacology. Copyright © John Wiley & Sons Ltd.
 
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.subjectadipokine
 
dc.subjectCYP2C9
 
dc.subjectendothelial dysfunction
 
dc.subjecteNOS
 
dc.subjectlipocalin-2
 
dc.subjectobesity
 
dc.titleLipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibition
 
dc.typeArticle
 
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<contributor.author>Mak, TW</contributor.author>
<contributor.author>Tse, HF</contributor.author>
<contributor.author>Law, IKM</contributor.author>
<contributor.author>Huang, B</contributor.author>
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Author Affiliations
  1. The University of Hong Kong
  2. Ontario Cancer Institute University of Toronto