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Article: Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells

TitleChronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells
Authors
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
Citation
British Journal Of Pharmacology, 2011, v. 162 n. 7, p. 1564-1576 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/133325
ISSN
2014 Impact Factor: 4.842
2014 SCImago Journal Rankings: 1.844
PubMed Central ID
ISI Accession Number ID
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).

References
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DC FieldValueLanguage
dc.contributor.authorLee, MYKen_HK
dc.contributor.authorLi, Hen_HK
dc.contributor.authorXiao, Yen_HK
dc.contributor.authorZhou, Zen_HK
dc.contributor.authorXu, Aen_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.date.accessioned2011-05-11T08:31:23Z-
dc.date.available2011-05-11T08:31:23Z-
dc.date.issued2011en_HK
dc.identifier.citationBritish Journal Of Pharmacology, 2011, v. 162 n. 7, p. 1564-1576en_HK
dc.identifier.issn0007-1188en_HK
dc.identifier.urihttp://hdl.handle.net/10722/133325-
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.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.subjectA-FABPen_HK
dc.subjectatherosclerosisen_HK
dc.subjectendothelial dysfunctionen_HK
dc.subjectendothelium-dependent relaxationen_HK
dc.subjecteNOSen_HK
dc.subjectnitric oxideen_HK
dc.titleChronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0007-1188&volume=162&issue=7&spage=1564&epage=1576&date=2011&atitle=Chronic+administration+of+BMS309403+improves+endothelial+function+in+apolipoprotein+E-deficient+mice+and+in+cultured+human+endothelial+cells-
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1111/j.1476-5381.2010.01158.xen_HK
dc.identifier.pmid21175571en_HK
dc.identifier.pmcidPMC3057294-
dc.identifier.scopuseid_2-s2.0-79952386370en_HK
dc.identifier.hkuros184803en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952386370&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume162en_HK
dc.identifier.issue7en_HK
dc.identifier.spage1564en_HK
dc.identifier.epage1576en_HK
dc.identifier.isiWOS:000288018100010-
dc.publisher.placeUnited Kingdomen_HK
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.identifier.scopusauthoridLee, MYK=22980015700en_HK
dc.identifier.scopusauthoridLi, H=44161094300en_HK
dc.identifier.scopusauthoridXiao, Y=36464707600en_HK
dc.identifier.scopusauthoridZhou, Z=35254771000en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK

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