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.

Oxidized Low-Density Lipoprotein-Induced Cyclophilin A Secretion Requires ROCK-Dependent Diphosphorylation of Myosin Light Chain

“…ox-LDL induces ROS in VSMC [8,9,10]. Therefore, we examined whether ox-LDL would induce CyPA secretion by Western blot analysis of CM.…”

“…CyPA can be secreted from RASMC in response to the ROS inducer LY83583 [11,12]. ox-LDL, as a proatherogenic factor, induces intracellular production of ROS in various cell types such as VSMC [8,9,10] and macrophages [26,27,28]. It has been reported that ox-LDL induces CyPA secretion from THP-1 via an unknown mechanism [29].…”

“…Oxidized low-density lipoprotein (ox-LDL) promotes intracellular production of reactive oxygen species (ROS) in VSMC [8,9,10]. Previous studies have shown that ROS can induce CyPA secretion from rat aortic smooth muscle cells (RASMC) through signaling pathways involving vesicle transportation, actin remodeling, and myosin II activity [11,12].…”

Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids

“…They were identified as VSMC by their characteristic hill-andvalley growth pattern and immunohistochemistry for VSMC-specific β-actin. The primary cultured human VSMC were used to generate an immortalized cell line by using SV40T antigen, SV40T-expressing human VSMC retain expression of contractile phenotype markers including smooth muscle β-actin and smMHC to passage 10 and higher as we previously described [6]. For all experiments passage 7-17 SV40T-expressing human VSMC culture were used.…”

PPARδ modulates oxLDL-induced apoptosis of vascular smooth muscle cells through a TGF-β/FAK signaling axis

“…Apoptosis is regulated in VSMCs by interactions between the local cells and cytokine environment within the arterial wall, and the expression of pro-and anti-apoptotic proteins by the cells (Bennett, 1999). Oxidized low-density lipoprotein (oxLDL), an atherogenic substance commonly present in atherosclerotic lesions, induces apoptosis in cultured VSMCs (Uchida et al, 2013;Larroque-Cardoso et al, 2013), endothelial cells (Dimmeler et al, 1997), and macrophages (Hardwick et al, 1996). The pathway for oxLDL-induced apoptosis includes activation of a complex cascade of kinases and changes in expression of Bcl-2 family genes (Cheng et al, 2007).…”