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Oxidized low-density lipoprotein activates p66Shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase C-beta, and c-Jun N-terminal kinase kinase in human endothelial cells.


Shi, Yi; Cosentino, Francesco; Camici, Giovanni G; Akhmedov, Alexander; Vanhoutte, Paul M; Tanner, Felix C; Lüscher, Thomas F (2011). Oxidized low-density lipoprotein activates p66Shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase C-beta, and c-Jun N-terminal kinase kinase in human endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(9):2090-2097.

Abstract

Objective: Deletion of the mitochondrial gene p66Shc 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 p66Shc 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 p66Shc at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66Shc 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, p66Shc silencing blunted oxLDL-induced O2−. production, underscoring the critical role of p66Shc in oxLDL-induced oxidative stress in endothelial cells.

Conclusion: In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66Shc. Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66Shc.

Abstract

Objective: Deletion of the mitochondrial gene p66Shc 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 p66Shc 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 p66Shc at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66Shc 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, p66Shc silencing blunted oxLDL-induced O2−. production, underscoring the critical role of p66Shc in oxLDL-induced oxidative stress in endothelial cells.

Conclusion: In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66Shc. Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66Shc.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:20 Jul 2012 10:58
Last Modified:05 Apr 2016 15:49
Publisher:Lippincott Wiliams & Wilkins
ISSN:1079-5642
Funders:Swiss National Research Foundation (Grant 3100-06811802/1 to T.F.L., Grant 3100-30130500 to G.G.C.), Swiss Heart Foundation, MERCATOR Schweiz Foundation, Fondazione Roma, Italy
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1161/ATVBAHA.111.229260
PubMed ID:21817106

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