title: Quercetin protects macrophages from oxidized low-density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress-C/EBP homologous protein pathway.
abstract: Quercetin (QUE), a member of the bioflavonoid family, has been proposed to have antioxidative, anti-inflammatory and antihypertensive properties. This study was designed to investigate the protective effect of QUE on oxidized low-density lipoprotein (ox-LDL)-induced cytotoxicity in RAW264.7 macrophages and specifically the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway-mediated apoptosis. Our results showed that treatment with QUE (20, 40 and 80 μmol/L) significantly attenuated ox-LDL-induced cholesterol accumulation in macrophages and foam cell formation in a dose-dependent manner. Similar to tunicamycin (TM), a classical ER stress inducer, ox-LDL reduced cell viability and induced apoptosis in RAW264.7 macrophages. The cytotoxic effects of ox-LDL and TM were signiﬁcantly inhibited by QUE treatment. Interestingly, we found that QUE also signiﬁcantly suppressed the ox-LDL- and TM-induced activation of ER stress signaling events, including the phosphorylation of inositol-requiring enzyme 1 (IRE1), translocation of activating transcription factor 6 (ATF6) from the cytoplasm to the nucleus and upregulation of X-box-binding protein 1. In addition, exposure of RAW264.7 macrophages to ox-LDL or TM resulted in a significant increase in the expression of CHOP, a transcription factor regulated by IRE1 and ATF6 under conditions of ER stress, as well as a decrease in Bcl-2 transcript and protein concentrations. QUE blocked these effects in a dose-dependent manner. These data indicate that QUE can protect RAW264.7 cells from ox-LDL-induced apoptosis and that the mechanism at least partially involves its ability to inhibit the ER stress-CHOP signaling pathway.
authors: Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, China.
authors: Shutong
authors: S
authors: Yao
authors: Hui
authors: H
authors: Sang
authors: Guohua
authors: G
authors: Song
authors: Nana
authors: N
authors: Yang
authors: Qinghua
authors: Q
authors: Liu
authors: Ying
authors: Y
authors: Zhang
authors: Peng
authors: P
authors: Jiao
authors: Chuanlong
authors: C
authors: Zong
authors: Shucun
authors: S
authors: Qin
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D018384:Oxidative Stress; D010766:Phosphorylation; D011794:Quercetin / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D011794:Quercetin