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

Yao, Shutong; Tian, Hua; Miao, Cheng; Zhang, Da Wei; Zhao, Li; Li, Yanyan; Yang, Ning; Jiao, Peng; Song, Hui; Guo, Shoudong; Wang, Yiwei; Qin, Shucun

doi:10.1194/jlr.m055400

Cited by 51 publications

(46 citation statements)

References 40 publications

(56 reference statements)

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“…CHOP can mediate macrophage apoptosis and contribute to the instability of atherosclerotic plaques (15)(16)(17). We have previously shown that ox-LDL can induce macrophage apoptosis by upregulating CHOP expression (18,19). Here, we investigated the potential role of the ER stress-CHOP pathway in ox-HDLinduced macrophage apoptosis.…”

Section: Cell Culture and Sirna Transfectionmentioning

confidence: 99%

“…CHOP, a specific proapoptotic molecule regulated by ATF6 and PERK under ER stress, has been demonstrated to play a crucial role in macrophage apoptosis and the destabilization of advanced atherosclerotic lesions, whereas CHOP deficiency inhibits macrophage apoptosis and reduces plaque necrosis in advanced atherosclerotic plaques (15)(16)(17). Our previous studies have shown that ox-LDL induces CHOP-mediated macrophage apoptosis by activating ATF6 and PERK pathways, whereas D4F, an apolipoprotein A-I mimetic peptide, alleviates macrophage-derived foam cell apoptosis by inhibiting the ER stress-CHOP pathway (18,19). In this study, we found that as with TM, ox-HDL not only induced macrophage injury and apoptosis but also activated an ER stress pathway, as assessed by the increased nuclear translocation of ATF6, phosphorylation of PERK, and eIF2, as well as upregulation of GRP78 and CHOP.…”

Section: Hdl From Ms Patients Induces Oxidative Stress and Chop-mediamentioning

confidence: 99%

“…Because the accumulation of intracellular lipid induced by ox-LDL is an important inducer of ER stress-CHOP-mediated macrophage apotosis (18,19,24), we examined whether ox-HDL could be taken up by macrophages and induce foam cell formation. As is seen in Fig.…”

Section: Ox-hdl Induces Intracellular Lipid Accumulation In Raw2647 mentioning

confidence: 99%

“…Cell apoptosis was measured by annexin V-FITC/propidium iodide (PI) double-staining assay and TUNEL assay, as has been reported in our previous work (19). In brief, the treated cells were harvested, washed with PBS, and then incubated in 500 l binding buffer containing 5 µl annexin V-FITC and 5 µl PI for 15 min in the dark at room temperature.…”

Section: Cell Apoptosis Measurementmentioning

confidence: 99%

“…Our previous studies have proven that minimally modified LDL (mm-LDL) and ox-LDL can induce cholesterol accumulation in macrophages and subsequently stimulate ER stress (18,19,23,26). In this work, we showed that ox-HDL could be taken up by macrophages and cause a significant increase in lipid accumulation but was less potent than was ox-LDL in promoting the macrophage-derived foam cell formation, suggesting that the effect of ox-HDL to induce macrophage-derived foam cell formation is much less than that of ox-LDL.…”

Section: Hdl From Ms Patients Induces Oxidative Stress and Chop-mediamentioning

confidence: 99%

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Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Yao¹,

Tian²,

Zhao³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Atherosclerosis, one of the prime causes of heart attack and stroke, has been well known as a lipid-driven inflammatory disease characterized by macrophage accumulation in subendothelial space. Apoptosis of macrophage-derived foam cells, especially in advanced atherosclerotic lesions where phagocytic clearance of dead and dying cells is defective, results in acellular necrotic lesions that are prone to plaque rupture and thrombosis formation, leading to the majority of acute vascular events (1). Thus, deeper understanding of the mechanisms of macrophage apoptosis may pave the way for developing novel therapeutic strategies to effectively prevent atherosclerotic plaque rupture and subsequent clinical complications (2). Oxidized LDL (ox-LDL) has been recognized as a major inducer, promoting foam cell formation and apoptosis in macrophages (3). In contrast, HDL exerts antiatherogenic functions such as promoting reverse cholesterol transport, suppressing inflammation, inhibiting LDL oxidation, and increasing endothelial nitric oxide production (4). However, accumulating evidence suggests that HDL, like LDL, is also susceptible to oxidative modification. Oxidized HDL Abstract Oxidized HDL (ox-HDL), unlike native HDL that exerts antiatherogenic effects, plays a proatherogenic role. However, the underlying mechanisms are not completely understood. This study was designed to explore the inductive effect of ox-HDL on endoplasmic reticulum (ER) stress-CCAAT-enhancer-binding protein homologous protein (CHOP)-mediated macrophage apoptosis and its upstream mechanisms. Our results showed that ox-HDL could be ingested by macrophages, causing intracellular lipid accumulation. As with tunicamycin (an ER stress inducer), ox-HDL induced macrophage apoptosis with concomitant activation of ER stress pathway, including nuclear translocation of activating transcription factor 6, phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2, and upregulation of glucose-regulated protein 78 and CHOP, which were inhibited by 4-phenylbutyric acid (PBA, an ER stress inhibitor) and CHOP gene silencing. Additionally, diphenyleneiodonium (DPI, an oxidative stress inhibitor), probucol (a reactive oxygen species scavenger), and toll-like receptor 4 (TLR4) silencing reduced ox-HDL-induced macrophage apoptosis, oxidative stress, and CHOP upregulation. Moreover, HDL isolated from patients with metabolic syndrome induced macrophage apoptosis, oxidative stress, and CHOP upregulation, which were blocked by PBA and DPI. These data indicate that ox-HDL may activate ER stress-CHOP-induced apoptotic pathway in macrophages via enhanced oxidative stress and that this pathway may be mediated by TLR4.

show abstract

Section: Cell Culture and Sirna Transfectionmentioning

confidence: 99%

Section: Hdl From Ms Patients Induces Oxidative Stress and Chop-mediamentioning

confidence: 99%

Section: Ox-hdl Induces Intracellular Lipid Accumulation In Raw2647 mentioning

confidence: 99%

Section: Cell Apoptosis Measurementmentioning

confidence: 99%

Section: Hdl From Ms Patients Induces Oxidative Stress and Chop-mediamentioning

confidence: 99%

See 3 more Smart Citations

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Yao¹,

Tian²,

Zhao³

et al. 2017

Journal of Lipid Research

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show abstract

Diabetes and Atherosclerosis

Lopes‐Virella

Virella

2023

Contemporary Cardiology

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Apolipoprotein-AI and AIBP synergetic anti-inflammation as vascular diseases therapy: the new perspective

2021

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

Cited by 51 publications

References 40 publications

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Oxidized high density lipoprotein induces macrophage apoptosis via toll-like receptor 4-dependent CHOP pathway

Diabetes and Atherosclerosis

Apolipoprotein-AI and AIBP synergetic anti-inflammation as vascular diseases therapy: the new perspective

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