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Article: Oxidized low-density lipoprotein activates p66shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase c-β, and c-jun n-terminal kinase kinase in human endothelial cells
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TitleOxidized low-density lipoprotein activates p66shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase c-β, and c-jun n-terminal kinase kinase in human endothelial cells
 
AuthorsShi, Y4
Cosentino, F4 3 1
Camici, GG4
Akhmedov, A4
Vanhoutte, PM2
Tanner, FC4 3
Lüscher, TF4 3
 
Keywordsendothelium
lipoproteins
reactive oxygen species
 
Issue Date2011
 
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.lww.com/product/?1079-5642
 
CitationArteriosclerosis, Thrombosis, And Vascular Biology, 2011, v. 31 n. 9, p. 2090-2097 [How to Cite?]
DOI: http://dx.doi.org/10.1161/ATVBAHA.111.229260
 
AbstractObjective-: Deletion of the mitochondrial gene p66 protects from endothelial dysfunction and atherosclerotic plaque formation in mice fed a high-fat diet. However, the molecular mechanisms underlying this beneficial effect have not yet been delineated. The present study was designed to elucidate the proatherogenic mechanisms by which p66 mediates oxidized low-density lipoprotein (oxLDL) uptake by the endothelium, a critical step in plaque formation. Methods and results-: Incubation of human aortic endothelial cells with oxLDL led to phosphorylation of p66 at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66 phosphorylation, confirming that this effect is mediated by lectin-like oxLDL receptor-1. OxLDL also increased phosphorylation of protein kinase C β2 (PKCβ2) at both Thr641 and Ser660, as well as c-Jun N-terminal kinase (JNK). Furthermore, inhibition of PKCβ2 prevented the activation of JNK, suggesting that PKCβ2 is upstream of JNK. Finally, p66 silencing blunted oxLDL-induced O2 production, underscoring the critical role of p66 in oxLDL-induced oxidative stress in endothelial cells. Conclusion-: In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66. Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66. © 2011 American Heart Association. All rights reserved.
 
ISSN1079-5642
2013 Impact Factor: 5.533
 
DOIhttp://dx.doi.org/10.1161/ATVBAHA.111.229260
 
ISI Accession Number IDWOS:000293955200028
Funding AgencyGrant Number
Swiss National Research Foundation3100-06811802/1
3100-30130500
Swiss Heart Foundation
MERCATOR Schweiz Foundation
Fondazione Roma, Italy
strategic alliance of Pfizer, New York
Funding Information:

This study was supported by grants from the Swiss National Research Foundation (Grant 3100-06811802/1 to T.F.L., Grant 3100-30130500 to G.G.C.); the Swiss Heart Foundation; the MERCATOR Schweiz Foundation; and the Fondazione Roma, Italy (to F.C.) and by a strategic alliance of Pfizer, New York.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorShi, Y
 
dc.contributor.authorCosentino, F
 
dc.contributor.authorCamici, GG
 
dc.contributor.authorAkhmedov, A
 
dc.contributor.authorVanhoutte, PM
 
dc.contributor.authorTanner, FC
 
dc.contributor.authorLüscher, TF
 
dc.date.accessioned2011-09-23T05:52:27Z
 
dc.date.available2011-09-23T05:52:27Z
 
dc.date.issued2011
 
dc.description.abstractObjective-: Deletion of the mitochondrial gene p66 protects from endothelial dysfunction and atherosclerotic plaque formation in mice fed a high-fat diet. However, the molecular mechanisms underlying this beneficial effect have not yet been delineated. The present study was designed to elucidate the proatherogenic mechanisms by which p66 mediates oxidized low-density lipoprotein (oxLDL) uptake by the endothelium, a critical step in plaque formation. Methods and results-: Incubation of human aortic endothelial cells with oxLDL led to phosphorylation of p66 at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66 phosphorylation, confirming that this effect is mediated by lectin-like oxLDL receptor-1. OxLDL also increased phosphorylation of protein kinase C β2 (PKCβ2) at both Thr641 and Ser660, as well as c-Jun N-terminal kinase (JNK). Furthermore, inhibition of PKCβ2 prevented the activation of JNK, suggesting that PKCβ2 is upstream of JNK. Finally, p66 silencing blunted oxLDL-induced O2 production, underscoring the critical role of p66 in oxLDL-induced oxidative stress in endothelial cells. Conclusion-: In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66. Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66. © 2011 American Heart Association. All rights reserved.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationArteriosclerosis, Thrombosis, And Vascular Biology, 2011, v. 31 n. 9, p. 2090-2097 [How to Cite?]
DOI: http://dx.doi.org/10.1161/ATVBAHA.111.229260
 
dc.identifier.doihttp://dx.doi.org/10.1161/ATVBAHA.111.229260
 
dc.identifier.epage2097
 
dc.identifier.hkuros195639
 
dc.identifier.isiWOS:000293955200028
Funding AgencyGrant Number
Swiss National Research Foundation3100-06811802/1
3100-30130500
Swiss Heart Foundation
MERCATOR Schweiz Foundation
Fondazione Roma, Italy
strategic alliance of Pfizer, New York
Funding Information:

This study was supported by grants from the Swiss National Research Foundation (Grant 3100-06811802/1 to T.F.L., Grant 3100-30130500 to G.G.C.); the Swiss Heart Foundation; the MERCATOR Schweiz Foundation; and the Fondazione Roma, Italy (to F.C.) and by a strategic alliance of Pfizer, New York.

 
dc.identifier.issn1079-5642
2013 Impact Factor: 5.533
 
dc.identifier.issue9
 
dc.identifier.pmid21817106
 
dc.identifier.scopuseid_2-s2.0-80052175705
 
dc.identifier.spage2090
 
dc.identifier.urihttp://hdl.handle.net/10722/139602
 
dc.identifier.volume31
 
dc.languageeng
 
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.lww.com/product/?1079-5642
 
dc.publisher.placeUnited States
 
dc.relation.ispartofArteriosclerosis, Thrombosis, and Vascular Biology
 
dc.relation.referencesReferences in Scopus
 
dc.rightsThis is a non-final version of an article published in final form in (provide complete journal citation)
 
dc.subject.meshEndothelial Cells - metabolism
 
dc.subject.meshJNK Mitogen-Activated Protein Kinases - metabolism
 
dc.subject.meshLipoproteins, LDL - physiology
 
dc.subject.meshProtein Kinase C - metabolism
 
dc.subject.meshScavenger Receptors, Class E - metabolism
 
dc.subjectendothelium
 
dc.subjectlipoproteins
 
dc.subjectreactive oxygen species
 
dc.titleOxidized low-density lipoprotein activates p66shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase c-β, and c-jun n-terminal kinase kinase in human endothelial cells
 
dc.typeArticle
 
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<contributor.author>Vanhoutte, PM</contributor.author>
<contributor.author>Tanner, FC</contributor.author>
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Author Affiliations
  1. Azienda Ospedaliera Sant'Andrea
  2. The University of Hong Kong
  3. UniversitatsSpital Zurich
  4. Universität Zürich