Article: Lipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibition
| Title | Lipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibition | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Authors | Liu, JTC1 Song, E1 Xu, A1 Berger, T2 Mak, TW2 Tse, HF1 Law, IKM1 Huang, B1 Liang, Y1 Vanhoutte, PM1 Wang, Y1 | ||||||||
| Keywords | adipokine CYP2C9 endothelial dysfunction eNOS lipocalin-2 obesity | ||||||||
| Issue Date | 2012 | ||||||||
| Publisher | John 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?] DOI: http://dx.doi.org/10.1111/j.1476-5381.2011.01587.x | ||||||||
| 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. | ||||||||
| ISSN | 0007-1188 2011 Impact Factor: 4.409 2011 SCImago Journal Rankings: 0.406 | ||||||||
| DOI | http://dx.doi.org/10.1111/j.1476-5381.2011.01587.x | ||||||||
| ISI Accession Number ID | WOS:000298481200018
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). | ||||||||
| PubMed Central ID | PMC3268203 | ||||||||
| References | References in Scopus |
| dc.contributor.author | Liu, JTC | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| dc.contributor.author | Song, E | ||||||||
| dc.contributor.author | Xu, A | ||||||||
| dc.contributor.author | Berger, T | ||||||||
| dc.contributor.author | Mak, TW | ||||||||
| dc.contributor.author | Tse, HF | ||||||||
| dc.contributor.author | Law, IKM | ||||||||
| dc.contributor.author | Huang, B | ||||||||
| dc.contributor.author | Liang, Y | ||||||||
| dc.contributor.author | Vanhoutte, PM | ||||||||
| dc.contributor.author | Wang, Y | ||||||||
| dc.date.accessioned | 2011-07-27T01:30:26Z | ||||||||
| dc.date.available | 2011-07-27T01:30:26Z | ||||||||
| dc.date.issued | 2012 | ||||||||
| dc.description.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. | ||||||||
| dc.description.nature | link_to_OA_fulltext | ||||||||
| dc.identifier.citation | British 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.doi | http://dx.doi.org/10.1111/j.1476-5381.2011.01587.x | ||||||||
| dc.identifier.epage | 531 | ||||||||
| dc.identifier.hkuros | 187316 | ||||||||
| dc.identifier.hkuros | 195686 | ||||||||
| dc.identifier.isi | WOS:000298481200018
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.issn | 0007-1188 2011 Impact Factor: 4.409 2011 SCImago Journal Rankings: 0.406 | ||||||||
| dc.identifier.issue | 2 | ||||||||
| dc.identifier.pmcid | PMC3268203 | ||||||||
| dc.identifier.pmid | 21740414 | ||||||||
| dc.identifier.scopus | eid_2-s2.0-83755172751 | ||||||||
| dc.identifier.spage | 520 | ||||||||
| dc.identifier.uri | http://hdl.handle.net/10722/135237 | ||||||||
| dc.identifier.volume | 165 | ||||||||
| dc.language | eng | ||||||||
| dc.publisher | John 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.place | United Kingdom | ||||||||
| dc.relation.ispartof | British Journal of Pharmacology | ||||||||
| dc.relation.references | References in Scopus | ||||||||
| dc.rights | British Journal of Pharmacology. Copyright © John Wiley & Sons Ltd. | ||||||||
| dc.subject.mesh | Aorta, Thoracic - drug effects - metabolism - physiopathology | ||||||||
| dc.subject.mesh | Endothelium, Vascular - drug effects - physiopathology | ||||||||
| dc.subject.mesh | Lipocalins - genetics - physiology | ||||||||
| dc.subject.mesh | Obesity - metabolism - physiopathology | ||||||||
| dc.subject.mesh | Oncogene Proteins - deficiency - genetics - physiology | ||||||||
| dc.subject | adipokine | ||||||||
| dc.subject | CYP2C9 | ||||||||
| dc.subject | endothelial dysfunction | ||||||||
| dc.subject | eNOS | ||||||||
| dc.subject | lipocalin-2 | ||||||||
| dc.subject | obesity | ||||||||
| dc.title | Lipocalin-2 deficiency prevents endothelial dysfunction associated with dietary obesity: Role of cytochrome P450 2C inhibition | ||||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong
- Ontario Cancer Institute