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Article: Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells
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TitleChronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells
 
AuthorsLee, MYK1
Li, H1
Xiao, Y2
Zhou, Z2
Xu, A1
Vanhoutte, PM1
 
KeywordsA-FABP
atherosclerosis
endothelial dysfunction
endothelium-dependent relaxation
eNOS
nitric oxide
 
Issue Date2011
 
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, 2011, v. 162 n. 7, p. 1564-1576 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1476-5381.2010.01158.x
 
AbstractBACKGROUND AND PURPOSE Adipocyte fatty acid-binding protein (A-FABP) is up-regulated in regenerated endothelial cells and modulates inflammatory responses in macrophages. Endothelial dysfunction accompanying regeneration is accelerated by hyperlipidaemia. Here, we investigate the contribution of A-FABP to the pathogenesis of endothelial dysfunction in the aorta of apolipoprotein E-deficient (ApoE -/-) mice and in cultured human endothelial cells. EXPERIMENTAL APPROACH A-FABP was measured in aortae of ApoE -/-mice and human endothelial cells by RT-PCR, immunostaining and immunoblotting. Total and phosphorylated forms of endothelial nitric oxide synthase (eNOS) were measured by immunoblotting. Changes in isometric tension were measured in rings of mice aortae KEY RESULTS A-FABP was expressed in aortic endothelium of ApoE -/- mice aged 12 weeks and older, but not at 8 weeks or in C57 wild-type mice. Reduced endothelium-dependent relaxations to acetylcholine, UK14304 (selective α 2-adrenoceptor agonist) and A23187 (calcium ionophore) and decreased protein presence of phosphorylated and total eNOS were observed in aortae of 18 week-old ApoE -/- mice compared with age-matched controls. A 6 week treatment with the A-FABP inhibitor, BMS309403, started in 12 week-old mice, improved endothelial function, phosphorylated and total eNOS and reduced plasma triglyceride levels but did not affect endothelium-independent relaxations. The beneficial effect of BMS309403 on UK14304-induced relaxations was attenuated by Pertussis toxin. In cultured human microvascular endothelial cells, lipid-induced A-FABP expression was associated with reduced phosphorylated eNOS and NO production and was reversed by BMS309403. CONCLUSIONS AND IMPLICATIONS Elevated expression of A-FABP in endothelial cells contributes to their dysfunction both in vivo and in vitro. © 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.1476-5381.2010.01158.x
 
PubMed Central IDPMC3057294
 
ISI Accession Number IDWOS:000288018100010
Funding AgencyGrant Number
University of Hong Kong
Research Grant Council of Hong KongHKU200707176115
HKU7772/08 M
HKU 2/07C
Research Centre of Heart, Brain, Hormone & Healthy Aging of the University of Hong Kong
NSFC/GRCN_HKU 735/08
Funding Information:

This work was supported in part by grants from the Small Project Funding from the University of Hong Kong, the Research Grant Council of Hong Kong (HKU200707176115 and HKU7772/08 M), the Research Centre of Heart, Brain, Hormone & Healthy Aging of the University of Hong Kong, the Collaborative Research Fund from Research Grant Council of Hong Kong (HKU 2/07C), and the NSFC/GRC joint research scheme (Project No: N_HKU 735/08).

 
ReferencesReferences in Scopus
 
GrantsAdipocyte fatty acid binding protein as a novel diagnostic marker and therapeutic target to combat vascular complications of diabetes: mechanisms and clinical implications
Vascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention
 
DC FieldValue
dc.contributor.authorLee, MYK
 
dc.contributor.authorLi, H
 
dc.contributor.authorXiao, Y
 
dc.contributor.authorZhou, Z
 
dc.contributor.authorXu, A
 
dc.contributor.authorVanhoutte, PM
 
dc.date.accessioned2011-05-11T08:31:23Z
 
dc.date.available2011-05-11T08:31:23Z
 
dc.date.issued2011
 
dc.description.abstractBACKGROUND AND PURPOSE Adipocyte fatty acid-binding protein (A-FABP) is up-regulated in regenerated endothelial cells and modulates inflammatory responses in macrophages. Endothelial dysfunction accompanying regeneration is accelerated by hyperlipidaemia. Here, we investigate the contribution of A-FABP to the pathogenesis of endothelial dysfunction in the aorta of apolipoprotein E-deficient (ApoE -/-) mice and in cultured human endothelial cells. EXPERIMENTAL APPROACH A-FABP was measured in aortae of ApoE -/-mice and human endothelial cells by RT-PCR, immunostaining and immunoblotting. Total and phosphorylated forms of endothelial nitric oxide synthase (eNOS) were measured by immunoblotting. Changes in isometric tension were measured in rings of mice aortae KEY RESULTS A-FABP was expressed in aortic endothelium of ApoE -/- mice aged 12 weeks and older, but not at 8 weeks or in C57 wild-type mice. Reduced endothelium-dependent relaxations to acetylcholine, UK14304 (selective α 2-adrenoceptor agonist) and A23187 (calcium ionophore) and decreased protein presence of phosphorylated and total eNOS were observed in aortae of 18 week-old ApoE -/- mice compared with age-matched controls. A 6 week treatment with the A-FABP inhibitor, BMS309403, started in 12 week-old mice, improved endothelial function, phosphorylated and total eNOS and reduced plasma triglyceride levels but did not affect endothelium-independent relaxations. The beneficial effect of BMS309403 on UK14304-induced relaxations was attenuated by Pertussis toxin. In cultured human microvascular endothelial cells, lipid-induced A-FABP expression was associated with reduced phosphorylated eNOS and NO production and was reversed by BMS309403. CONCLUSIONS AND IMPLICATIONS Elevated expression of A-FABP in endothelial cells contributes to their dysfunction both in vivo and in vitro. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationBritish Journal Of Pharmacology, 2011, v. 162 n. 7, p. 1564-1576 [How to Cite?]
DOI: http://dx.doi.org/10.1111/j.1476-5381.2010.01158.x
 
dc.identifier.doihttp://dx.doi.org/10.1111/j.1476-5381.2010.01158.x
 
dc.identifier.epage1576
 
dc.identifier.hkuros184803
 
dc.identifier.isiWOS:000288018100010
Funding AgencyGrant Number
University of Hong Kong
Research Grant Council of Hong KongHKU200707176115
HKU7772/08 M
HKU 2/07C
Research Centre of Heart, Brain, Hormone & Healthy Aging of the University of Hong Kong
NSFC/GRCN_HKU 735/08
Funding Information:

This work was supported in part by grants from the Small Project Funding from the University of Hong Kong, the Research Grant Council of Hong Kong (HKU200707176115 and HKU7772/08 M), the Research Centre of Heart, Brain, Hormone & Healthy Aging of the University of Hong Kong, the Collaborative Research Fund from Research Grant Council of Hong Kong (HKU 2/07C), and the NSFC/GRC joint research scheme (Project No: N_HKU 735/08).

 
dc.identifier.issn0007-1188
2012 Impact Factor: 5.067
2012 SCImago Journal Rankings: 1.488
 
dc.identifier.issue7
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC3057294
 
dc.identifier.pmid21175571
 
dc.identifier.scopuseid_2-s2.0-79952386370
 
dc.identifier.spage1564
 
dc.identifier.urihttp://hdl.handle.net/10722/133325
 
dc.identifier.volume162
 
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.projectAdipocyte fatty acid binding protein as a novel diagnostic marker and therapeutic target to combat vascular complications of diabetes: mechanisms and clinical implications
 
dc.relation.projectVascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention
 
dc.relation.referencesReferences in Scopus
 
dc.rightsBritish Journal of Pharmacology. Copyright © John Wiley & Sons Ltd.
 
dc.subjectA-FABP
 
dc.subjectatherosclerosis
 
dc.subjectendothelial dysfunction
 
dc.subjectendothelium-dependent relaxation
 
dc.subjecteNOS
 
dc.subjectnitric oxide
 
dc.titleChronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Second Xiangya Hospital of Central-South University