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Article: APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice

TitleAPPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice
Authors
Issue Date2011
PublisherAmerican Diabetes Association. The Journal's web site is located at http://diabetes.diabetesjournals.org/
Citation
Diabetes, 2011, v. 60 n. 11, p. 3044-3054 How to Cite?
AbstractOBJECTIVE - Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)-dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells. RESEARCH DESIGN AND METHODS - Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1's physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells. RESULTS - Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1-dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal-related kinase (ERK) 1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1. CONCLUSIONS - APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium. © 2011 by the American Diabetes Association.
Persistent Identifierhttp://hdl.handle.net/10722/143763
ISSN
2015 Impact Factor: 8.784
2015 SCImago Journal Rankings: 5.185
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong KongHKU 779707M
HKU 2/07C
HKU4/CRF/10
National Natural Science Foundation of ChinaNSF 30771024
30811120429
Funding Information:

A.X. has received a grant from the general research fund of the Research Grants Council of Hong Kong (HKU 779707M). This study has received support from the collaborative research fund of the Research Grants Council of Hong Kong (HKU 2/07C and HKU4/CRF/10) and the General Program of the National Natural Science Foundation of China (NSF 30771024 and 30811120429).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorWang, Yen_HK
dc.contributor.authorCheng, KKYen_HK
dc.contributor.authorLam, KSLen_HK
dc.contributor.authorWu, Den_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorHuang, Yen_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.contributor.authorSweeney, Gen_HK
dc.contributor.authorLi, Yen_HK
dc.contributor.authorXu, Aen_HK
dc.date.accessioned2011-12-21T08:54:08Z-
dc.date.available2011-12-21T08:54:08Z-
dc.date.issued2011en_HK
dc.identifier.citationDiabetes, 2011, v. 60 n. 11, p. 3044-3054en_HK
dc.identifier.issn0012-1797en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143763-
dc.description.abstractOBJECTIVE - Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)-dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells. RESEARCH DESIGN AND METHODS - Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1's physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells. RESULTS - Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1-dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal-related kinase (ERK) 1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1. CONCLUSIONS - APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium. © 2011 by the American Diabetes Association.en_HK
dc.languageengen_US
dc.publisherAmerican Diabetes Association. The Journal's web site is located at http://diabetes.diabetesjournals.org/en_HK
dc.relation.ispartofDiabetesen_HK
dc.subject.meshAdaptor Proteins, Signal Transducing - antagonists and inhibitors - genetics - physiology-
dc.subject.meshEndothelin-1 - metabolism-
dc.subject.meshEndothelium, Vascular - drug effects - metabolism - physiopathology-
dc.subject.meshNitric Oxide - metabolism-
dc.subject.meshObesity - physiopathology-
dc.titleAPPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in miceen_HK
dc.typeArticleen_HK
dc.identifier.emailCheng, KKY: dorncky@hkucc.hku.hken_HK
dc.identifier.emailLam, KSL: ksllam@hku.hken_HK
dc.identifier.emailWang, Y: yuwanghk@hku.hken_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.authorityCheng, KKY=rp01672en_HK
dc.identifier.authorityLam, KSL=rp00343en_HK
dc.identifier.authorityWang, Y=rp00239en_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.2337/db11-0666en_HK
dc.identifier.pmid21926268-
dc.identifier.pmcidPMC3198090-
dc.identifier.scopuseid_2-s2.0-80755168862en_HK
dc.identifier.hkuros197853en_US
dc.identifier.hkuros213329-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80755168862&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume60en_HK
dc.identifier.issue11en_HK
dc.identifier.spage3044en_HK
dc.identifier.epage3054en_HK
dc.identifier.isiWOS:000296954600044-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectAPPL1 as a novel modulator of endothelial nitric oxide production and endothelium-dependent vasodilation-
dc.relation.projectA Multi-disciplinary Approach to Investigate Vascular Dysfunction in Obesity and Diabetes: From Molecular Mechanism to Therapeutic Intervention-
dc.relation.projectVascular dysfunction in obesity and diabetes: from risk prediction to therapeutic intervention-
dc.identifier.scopusauthoridWang, Y=7601517067en_HK
dc.identifier.scopusauthoridCheng, KKY=7402997599en_HK
dc.identifier.scopusauthoridLam, KSL=8082870600en_HK
dc.identifier.scopusauthoridWu, D=7404297751en_HK
dc.identifier.scopusauthoridWang, Y=34973733700en_HK
dc.identifier.scopusauthoridHuang, Y=34770945300en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK
dc.identifier.scopusauthoridSweeney, G=7102852659en_HK
dc.identifier.scopusauthoridLi, Y=35210753800en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK

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