title: 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.
abstract: OBJECTIVE
  Deletion of the mitochondrial gene p66(Shc) 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(Shc) mediates oxidized low-density lipoprotein (oxLDL) uptake by the endothelium, a critical step in plaque formation.
  
  
  RESULTS
  Incubation of human aortic endothelial cells with oxLDL led to phosphorylation of p66(Shc) at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66(Shc) phosphorylation, confirming that this effect is mediated by lectin-like oxLDL receptor-1. OxLDL also increased phosphorylation of protein kinase C β(2) (PKCβ(2)) at both Thr641 and Ser660, as well as c-Jun N-terminal kinase (JNK). Furthermore, inhibition of PKCβ(2) prevented the activation of JNK, suggesting that PKCβ2 is upstream of JNK. Finally, p66(Shc) silencing blunted oxLDL-induced O(2)(-·) production, underscoring the critical role of p66(Shc) in oxLDL-induced oxidative stress in endothelial cells.
  
  
  CONCLUSIONS
  In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66(Shc). Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66(Shc).
authors.affiliation: Cardiovascular Research, Institute of Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Francesco
authors.initials: F
authors.lastname: Cosentino
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.forename: Alexander
authors.initials: A
authors.lastname: Akhmedov
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: Felix C
authors.initials: FC
authors.lastname: Tanner
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
mesh_terms: D050197:Atherosclerosis / Q000209:etiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000502:physiology*; D019255:NADPH Oxidases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; C528024:SHC1 protein, human; D051127:Scavenger Receptors, Class E; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C099252:oxidized low density lipoprotein; D013481:Superoxides; D019255:NADPH Oxidases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048031:JNK Mitogen-Activated Protein Kinases