CCAAT/enhancer-binding protein beta (C/EBPβ) knockdown reduces inflammation, ER stress, and apoptosis, and promotes autophagy in oxLDL-treated RAW264.7 macrophage cells
| Autor: | Shaikh M. Rahman, Michael Rogowski, Christopher Ponce, M D Khurshidul Zahid, Naima Moustaid-Moussa, Mahua Choudhury |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry ATG5 Inflammation Apoptosis mTORC1 03 medical and health sciences Mice 0302 clinical medicine medicine Macrophage Animals Molecular Biology PI3K/AKT/mTOR pathway Foam cell Chemistry CCAAT-Enhancer-Binding Protein-beta Autophagy Cell Biology General Medicine Endoplasmic Reticulum Stress Cell biology Lipoproteins LDL 030104 developmental biology RAW 264.7 Cells Gene Expression Regulation 030220 oncology & carcinogenesis Gene Knockdown Techniques Unfolded protein response lipids (amino acids peptides and proteins) medicine.symptom Foam Cells |
| Zdroj: | Molecular and cellular biochemistry. 463(1-2) |
| ISSN: | 1573-4919 |
| Popis: | Atherosclerosis is associated with deregulated cholesterol metabolism and formation of macrophage foam cells. CCAAT/enhancer-binding protein beta (C/EBPβ) is a transcription factor, and its inhibition has recently been shown to prevent atherosclerosis development and foam cell formation. However, whether C/EBPβ regulates inflammation, endoplasmic reticulum (ER) stress, and apoptosis, in macrophage foam cells and its underlying molecular mechanism remains unknown. Here, we investigated the effect of C/EBPβ knockdown on proteins and genes implicated in inflammation, ER stress, apoptosis, and autophagy in macrophage foam cells. RAW264.7 macrophage cells were transfected with control and C/EBPβ-siRNA and then treated with nLDL and oxLDL. Key proteins and genes involved in inflammation, ER stress, apoptosis, and autophagy were analyzed by western blot and qPCR. We found that short interfering RNA (siRNA)-mediated knockdown of C/EBPβ attenuated atherogenic lipid-mediated induction of proteins and genes implicated in inflammation (P-NFkB-p65, NFkB-p65, and TNFα), ER stress (ATF4 and ATF6), and apoptosis (CHOP, caspase 1, 3, and 12). Interestingly, C/EBPβ knockdown upregulated the expression of autophagy proteins (LC3A/B-II, ATG5) and genes (LC3B, ATG5) but decreased the mammalian target of rapamycin (mTOR) protein phosphorylation and mTORC1 gene expression in oxLDL-loaded RAW264.7 macrophage cells. More importantly, treatment with rapamycin (inhibitor of mTOR) increased expression of proteins implicated in autophagy and cholesterol efflux in oxLDL-loaded RAW 264.7 macrophage cells. The present results suggest that C/EBPβ inactivation regulates macrophage foam cell formation in atherogenesis by reducing inflammation, ER stress, and apoptosis and by promoting autophagy and inactivating mTOR. |
| Databáze: | OpenAIRE |
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