Downregulation of activating transcription factor 4 attenuates lysophosphatidycholine-induced inflammation via the NF-κB pathway.

Lysophosphatidycholine (LPC) is the main active component in oxidized low-density lipoprotein (ox-LDL). The pathological function of ox-LDL has been broadly studied in atherosclerosis. However, the specific relationship between LPC-induced unfolded protein response (UPR) and inflammation in human umbilical vein endothelial cells (HUVECs) remains elusive. In this study, we found elevated serum levels of LPC in atherosclerotic patients. LPC stimulation resulted in elevated secretion of interleukin (IL)-6 and IL-8 in HUVECs, accompanied with the activation of ER stress and NF-κB pathway. Additionally, suppression of ER stress by 4-phenylbutric acid (4-PBA), an ER stress inhibitor, alleviated the activation of the NF-κB pathway and secretion of inflammatory factors. Moreover, activating transcription factor 4 (ATF4) silencing inhibited the transcription and secretion of IL-6 and IL-8, and suppressed the adhesion of THP-1 cells to HUVECs. Activation of the NF-κB pathway and expression of its upstream factors, including Toll like receptor 4 and cellular inhibitor of apoptosis, were also inhibited by ATF4 silencing. The present findings suggest that suppression of UPR alleviates LPC-induced HUVECs inflammation by inhibition of NF-κB pathway, and indicate ATF4 as a potential target for the treatment of atherosclerosis. Copyright © 2021 Elsevier B.V. All rights reserved.

Citation

Yingchao Gong, Qingfeng Li, Zetao Ma, Tingting Jin, Jun Lin, Qingbo Lv, Meihui Wang, Guosheng Fu, Shengjie Xu. Downregulation of activating transcription factor 4 attenuates lysophosphatidycholine-induced inflammation via the NF-κB pathway. European journal of pharmacology. 2021 Nov 15;911:174457

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PMID: 34582847

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