Role of protein kinase C δ in ER stress and apoptosis induced by oxidized LDL in human vascular smooth muscle cells

摘要

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 (PKC δ ) 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 PKC δ exhibited a protection towards oxLDL-induced apoptosis. OxLDL triggered the activation of PKC δ as shown by its phosphorylation and nuclear translocation. PKC δ activation was dependent on the reactive oxygen species generated by oxLDL. Moreover, we demonstrated that PKC δ participates in oxLDL-induced endoplasmic reticulum (ER) stress-dependent apoptotic signaling mainly through the IRE1 α /JNK pathway. Finally, the role of PKC δ in the development of atherosclerosis was supported by immunohistological analyses showing the colocalization of activated PKC δ with ER stress and lipid peroxidation markers in human atherosclerotic lesions. These findings highlight a role for PKC δ as a key regulator of oxLDL-induced ER stress-mediated apoptosis in VSMC, which may contribute to atherosclerotic plaque instability and rupture.