title: D4F alleviates macrophage-derived foam cell apoptosis by inhibiting CD36 expression and ER stress-CHOP pathway.
abstract: This study was designed to explore the protective effect of D4F, an apoA-I mimetic peptide, on oxidized LDL (ox-LDL)-induced endoplasmic reticulum (ER) stress-CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) pathway-mediated apoptosis in macrophages. Our results showed that treating apoE knockout mice with D4F decreased the serum ox-LDL level and apoptosis in atherosclerotic lesions with concomitant downregulation of cluster of differentiation 36 (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-LDL- or 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-LDL- or 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 the ER stress-CHOP pathway.
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China College of Basic Medical Sciences, Taishan Medical University, Taian 271000, China.
authors: Shutong
authors: S
authors: Yao
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China.
authors: Hua
authors: H
authors: Tian
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China.
authors: Cheng
authors: C
authors: Miao
authors: Departments of Pediatrics and Biochemistry, Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2S2, Canada.
authors: Da-Wei
authors: DW
authors: Zhang
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China Affiliated Hospital of Chengde Medical University, Chengde Medical University, Chengde 067000, China.
authors: Li
authors: L
authors: Zhao
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China.
authors: Yanyan
authors: Y
authors: Li
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China.
authors: Nana
authors: N
authors: Yang
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China.
authors: Peng
authors: P
authors: Jiao
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China College of Basic Medical Sciences, Taishan Medical University, Taian 271000, China.
authors: Hui
authors: H
authors: Sang
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China.
authors: Shoudong
authors: S
authors: Guo
authors: Affiliated Hospital of Chengde Medical University, Chengde Medical University, Chengde 067000, China.
authors: Yiwei
authors: Y
authors: Wang
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian 271000, China.
authors: Shucun
authors: S
authors: Qin
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology* / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000188:drug therapy; D001692:Biological Transport / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014415:Tunicamycin / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D015415:Biomarkers; D018955:CD36 Antigens; C465468:D-4F peptide; C497250:Ddit3 protein, mouse; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D014415:Tunicamycin; D051742:Transcription Factor CHOP
keywords: C/EBP homologous protein; apolipoprotein A-I mimetic peptide; apoptosis; cluster of differentiation 36; endoplasmic reticulum stress; oxidized low density lipoprotein
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