title: Role of protein kinase C δ in ER stress and apoptosis induced by oxidized LDL in human vascular smooth muscle cells.
abstract: During atherogenesis, excess amounts of low-density lipoproteins (LDL) accumulate in the subendothelial space where they undergo oxidative modifications. Oxidized LDL (oxLDL) alter the fragile balance between survival and death of vascular smooth muscle cells (VSMC) thereby leading to plaque instability and finally to atherothrombotic events. As protein kinase C δ (PKCδ) is pro-apoptotic in many cell types, we investigated its potential role in the regulation of VSMC apoptosis induced by oxLDL. We found that human VSMC silenced for PKCδ exhibited a protection towards oxLDL-induced apoptosis. OxLDL triggered the activation of PKCδ as shown by its phosphorylation and nuclear translocation. PKCδ activation was dependent on the reactive oxygen species generated by oxLDL. Moreover, we demonstrated that PKCδ participates in oxLDL-induced endoplasmic reticulum (ER) stress-dependent apoptotic signaling mainly through the IRE1α/JNK pathway. Finally, the role of PKCδ in the development of atherosclerosis was supported by immunohistological analyses showing the colocalization of activated PKCδ with ER stress and lipid peroxidation markers in human atherosclerotic lesions. These findings highlight a role for PKCδ as a key regulator of oxLDL-induced ER stress-mediated apoptosis in VSMC, which may contribute to atherosclerotic plaque instability and rupture.
authors: INSERM UMR 1048/I2MC, Toulouse, France.
authors: P
authors: P
authors: Larroque-Cardoso
authors: A
authors: A
authors: Swiader
authors: C
authors: C
authors: Ingueneau
authors: A
authors: A
authors: Nègre-Salvayre
authors: M
authors: M
authors: Elbaz
authors: M E
authors: ME
authors: Reyland
authors: R
authors: R
authors: Salvayre
authors: C
authors: C
authors: Vindis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases