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-kappa B pathway. Additionally, suppression of ER stress by 4-phenylbutric acid (4-PBA), an ER stress inhibitor, alleviated the activation of the NF-kappa B 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-kappa B 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-kappa B pathway, and indicate ATF4 as a potential target for the treatment of atherosclerosis.

Automated summary

The study revealed elevated levels of LPC in atherosclerotic patients, with LPC stimulation leading to increased secretion of inflammatory factors in HUVECs through activation of ER stress and the NF-kappa B pathway. This suggests that targeting ATF4 could be a potential treatment strategy for atherosclerosis by suppressing UPR and inhibiting inflammation.