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.

摘要

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.\ud\udMethods 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.\ud\udConclusion: 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.