Role of protein kinase C δ in ER stress and apoptosis induced by oxidized LDL in human vascular smooth muscle cells.
Role of protein kinase C δ in ER stress and apoptosis induced by oxidized LDL in human vascular smooth muscle cells.
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DOI：
10.1038/cddis.2013.47
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发表时间：
2013-02-28
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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在动脉粥样硬化过程中，过量的低密度脂蛋白（LDL）积聚在内皮下空间，并在那里进行氧化修饰。氧化LDL （oxLDL）改变血管平滑肌细胞（VSMC）生存和死亡之间的脆弱平衡，从而导致斑块不稳定，最终导致动脉粥样硬化血栓事件。由于蛋白激酶Cδ (PKCδ)在许多细胞类型中都是促凋亡的，我们研究了它在调节oxLDL诱导的VSMC凋亡中的潜在作用。我们发现PKCδ沉默的人VSMC对oxldl诱导的细胞凋亡具有保护作用。OxLDL通过磷酸化和核易位激活PKCδ。PKCδ的活化依赖于oxLDL产生的活性氧。此外，我们证明PKCδ主要通过IRE1α/JNK途径参与氧化低密度脂蛋白诱导的内质网（ER）应激依赖性凋亡信号传导。最后，PKCδ在动脉粥样硬化发展中的作用得到了免疫组织学分析的支持，该分析显示，在人类动脉粥样硬化病变中，活化的PKCδ与内质网应激和脂质过氧化标志物共定位。这些发现突出了PKCδ作为氧化低密度脂蛋白诱导内质网应激介导的VSMC凋亡的关键调节因子的作用，这可能有助于动脉粥样硬化斑块的不稳定和破裂。
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.
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影响因子：
8
作者：
Altenhofer, Sebastian;Kleikers, Pamela W. M.;Radermacher, Kim A.;Scheurer, Peter;Hermans, J. J. Rob;Schiffers, Paul;Ho, Heidi;Wingler, Kirstin;Schmidt, Harald H. H. W.
通讯作者：
Schmidt, Harald H. H. W.
DOI：
10.2741/3385
发表时间：
2009-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Reyland ME
通讯作者：
Reyland ME
影响因子：
12.4
作者：
Muller, C.;Salvayre, R.;Vindis, C.
通讯作者：
Vindis, C.
影响因子：
4
作者：
Qi, Xin;Mochly-Rosen, Daria
通讯作者：
Mochly-Rosen, Daria
DOI：
10.1152/ajpheart.00274.2009
发表时间：
2009-12-01
影响因子：
4.8
作者：
Kato, Kaori;Yamanouchi, Dai;Liu, Bo
通讯作者：
Liu, Bo