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.
Highlights
The apoptotic signaling triggered by oxidized low-density lipoproteins (oxLDL) is mediated through a complex sequence of signaling events that lead to activation of caspase-dependent or caspase-independent apoptotic pathways
We first investigated the involvement of Protein kinase C d (PKCd) in the apoptosis of human vascular smooth muscle cells treated with oxLDL
We report for the first time that PKCd is activated by oxLDL in human vascular smooth muscle cells (VSMC) and contributes to oxLDL-induced endoplasmic reticulum (ER) stress-dependent apoptotic signaling through the I IRE1a/JNK pathway
Summary
The apoptotic signaling triggered by oxLDL is mediated through a complex sequence of signaling events that lead to activation of caspase-dependent or caspase-independent apoptotic pathways. We previously reported that treatment of human VSMC with oxLDL induced a sustained rise of cytosolic calcium, leading to the activation of the intrinsic mitochondrial apoptotic pathway.[5,6] More recently, we showed in human vascular endothelial cells an interaction between the deregulation of cytosolic calcium and the endoplasmic reticulum (ER) stress in triggering the apoptotic response induced by oxLDL.[7] ER plays an essential role in sensing cellular stress (i.e., accumulation of misfolded proteins, potential redox or calcium deregulation) as it rapidly detects changes in cell homeostasis, and responds by eliciting UPR (unfolded protein response) via the activation of ER transmembrane sensors, PERK (double-stranded RNAdependent protein kinase (PKR)-like ER kinase), IRE1a (inositol-requiring 1a) and ATF6 (activating transcription factor 6). It has been shown that PKCd plays a crucial role in the propagation of TNFa-induced ER stress-mediated JNK activation and CHOP/GADD53 induction.[16] Hitherto, whether PKCd contributes to oxLDL-induced vascular SMC apoptosis and ER stress is not known. We provided evidence that activated PKCd is colocalized with ER stress and lipid peroxidation markers in human atherosclerotic lesions
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