D4F alleviates macrophage-derived foam cell apoptosis by inhibiting CD36 expression and endoplasmic reticulum stress-CHOP pathway

This study was designed to explore the protective effect of D4F, an apolipoprotein A-I mimetic peptide, on oxidized low-density lipoprotein (ox-LDL)-induced endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway-mediated apoptosis in macrophages. Our results showed that treating apoE mice with D4F decreased serum ox-LDL level and apoptosis in atherosclerotic lesions with concomitant downregulation of CD36 and inhibition of ER stress. In vitro, D4F inhibited macrophage-derived foam cell formation. Furthermore, like ER stress inhibitor 4-phenylbutyric acid (PBA), D4F inhibited ox-LDLor tunicamycin (TM, an ER stress inducer)-induced reduction in cell viability and increase in lactate dehydrogenase leakage, caspase-3 activation and apoptosis. Additionally, like PBA, D4F inhibited ox-LDLor TM-induced activation of ER stress response as assessed by the reduced nuclear translocation of activating transcription factor 6 and the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α as well as the downregulation of glucose regulated protein 78 and CHOP. Moreover, D4F mitigated ox-LDL uptake by macrophages and CD36 upregulation induced by ox-LDL or TM. These data indicate that D4F can alleviate the formation and apoptosis of macrophage-derived foam cells by suppressing CD36-mediated ox-LDL uptake and subsequent activation of ER stress-CHOP pathway.