Erythropoietin Suppresses the Formation of Macrophage Foam Cells

Lu, Kuo Yun; Ching, Li Chieh; Su, Kuo‐Hui; Yu, Yuan Bin; Kou, Yu Ru; Hsiao, Sheng Huang; Huang, Yu; Chen, Chien‐Yu; Cheng, Li; Pan, Ching Chian; Lee, Tzong‐Shyuan

doi:10.1161/circulationaha.109.876839

Cited by 62 publications

(55 citation statements)

References 38 publications

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“…Furthermore, we found that UFM1 did not affect the gene expression of cholesterol synthesis-related genes, including SREBP2, HMGCR, and LDLR. Our results are consistent with previous studies showing that induction expression of ABCA1 or ABCG1 would reduce the lipid accumulation in macrophage foam cells [34][35][36]53) . Together, these data suggest that the UFM1-induced reduction of macrophage cholesterol accumulation is not likely due to cholesterol uptake and inhibition of endogenous lipid synthesis and hydrolysis, but it is specifically dependent on ABCA1-and ABCG1-mediated cholesterol efflux.…”

Section: Acknowledgmentssupporting

confidence: 93%

“…Nuclear extracts were prepared using a previously reported method 34) . Western blot analysis was performed as previously described 35) .…”

Section: Western Blotmentioning

confidence: 99%

“…The pGL3-Renilla plasmid (Promega) was cotransfected as a control. Twenty-four hours after transfection, cells were treated with or without oxLDL for another 24 h. LXR agonist TO901317 (Ann Arbor, MI, USA) treatment was performed following previously described protocols 34) . The cells were then harvested and the luciferase activity was measured using the Dual-Luciferase Reporter Assay System (Promega), according to the manufacturer's recommendations.…”

Section: Ufm1 Prevents Macrophage Foam Cell Formationmentioning

confidence: 99%

“…The cells were then harvested and the luciferase activity was measured using the Dual-Luciferase Reporter Assay System (Promega), according to the manufacturer's recommendations. The luciferase activity was normalized to control Renilla construct expression, as previously reported 34) .…”

Section: Ufm1 Prevents Macrophage Foam Cell Formationmentioning

confidence: 99%

“…Once activated, LXRs induce an array of genes that are involved in cholesterol absorption, efflux, transport, and secretion 45,46) . Previous reports have suggested that ABCA1 and ABCG1 are LXR target gene s, and LXR -mediated transcriptional regulation is required for inducing these cholesterol transporters 34,53) . Therefore, we hypothesized that UFM1 might promote cholesterol efflux via LXR activation in the formation of macrophage foam cells.…”

Section: Acknowledgmentsmentioning

confidence: 99%

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UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Pang

Xiong

et al. 2015

J Atheroscler Thromb

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Aim: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. Methods: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE / mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. Results: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor (LXR ) activation, which was confirmed by the observation that LXR siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. Conclusions: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXR -dependent pathway.

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Section: Acknowledgmentssupporting

confidence: 93%

“…Nuclear extracts were prepared using a previously reported method 34) . Western blot analysis was performed as previously described 35) .…”

Section: Western Blotmentioning

confidence: 99%

Section: Ufm1 Prevents Macrophage Foam Cell Formationmentioning

confidence: 99%

Section: Ufm1 Prevents Macrophage Foam Cell Formationmentioning

confidence: 99%

Section: Acknowledgmentsmentioning

confidence: 99%

See 3 more Smart Citations

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Pang

Xiong

et al. 2015

J Atheroscler Thromb

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AMP‐activated protein kinase mediates erythropoietin‐induced activation of endothelial nitric oxide synthase

Hou

et al. 2012

Journal Cellular Physiology

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We investigated whether AMP-activated protein kinase (AMPK), a multi-functional regulator of energy homeostasis, participates in the regulation of erythropoietin (EPO)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with EPO increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC), and eNOS, as revealed by Western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the EPO-induced increase in the phosphorylation of AMPK, ACC, and eNOS, as well as nitric oxide (NO) production. Additionally, suppression of AMPK activation abolished EPO-induced EC proliferation, migration and tube formation. Immunoprecipitation analysis demonstrated that AMPK mediated the EPO-induced increase in the phosphorylation of β common receptor (βCR) and the formation of a βCR-AMPK-eNOS complex. In mice, inhibition of AMPK activation by compound C markedly decreased EPO-elicited angiogenesis in Matrigel plugs. Furthermore, the phosphorylation of AMPK and eNOS was significantly higher in aortas from EPO transgenic mice than wild-type mice. Moreover, treatment with EPO neutralizing antibody greatly reduced the exercise training-induced increase in phosphorylation of AMPK and eNOS in aortas of wild-type mice. Taken together, EPO may trigger AMPK-dependent signaling, which leads to enhanced phosphorylation of βCR and eNOS, increased βCR-AMPK-eNOS complex formation, NO production, and, ultimately, angiogenesis.

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Excess nitric oxide impairs liver X receptor α-ATP-binding cassette transporter A1-dependent cholesterol efflux in macrophage foam cells

Zhao¹,

Shyue

Lin

et al. 2013

J. Cell. Physiol.

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Excess nitric oxide (NO) promotes the progression of atherosclerosis by increasing the oxidation of low-density lipoprotein (LDL) and inflammatory responses. However, little is known about the impact of NO and its underlying molecular mechanism on lipid metabolism of macrophage foam cells. In this study, Oil-red O staining, cholesterol and triglyceride assay, Dil-oxidized LDL (oxLDL) binding assay, cholesterol efflux assay, real-time RT-PCR and Western blot analysis were used for in vitro experiments. Apolipoprotein E-deficient (apoE(-/-) ) and apoE and inducible nitric oxide synthase-deficient (apoE(-/-) iNOS(-/-) ) mice were as our in vivo models. Treatment with S-nitroso-N-acetyl-D,L-penicillamine (SNAP), an NO donor, exacerbated oxLDL-induced cholesterol accumulation in macrophages, because of reduced efficacy of cholesterol efflux. In addition, SNAP decreased the protein level of ATP-binding cassette transporter A1 (ABCA1) without affecting scavenger receptor type A (SR-A), CD36, ABCG1, or SR-B1 levels. This SNAP-mediated downregulation of ABCA1 was mainly through the effect of NO but not peroxynitrite. Furthermore, the SNAP-downregulated ABCA1 was due to the decrease in the liver X receptor α (LXRα)-dependent transcriptional regulation. Moreover, genetic deletion of iNOS increased the serum capacity of reverse cholesterol efflux and protein expression of LXRα, ABCA1, and SR-BI in aortas and retarded atherosclerosis in apoE(-/-) mice. Our findings provide new insights in the pro-atherogenic effect of excess NO on cholesterol metabolism in macrophages.

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Erythropoietin Suppresses the Formation of Macrophage Foam Cells

Cited by 62 publications

References 38 publications

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

AMP‐activated protein kinase mediates erythropoietin‐induced activation of endothelial nitric oxide synthase

Excess nitric oxide impairs liver X receptor α-ATP-binding cassette transporter A1-dependent cholesterol efflux in macrophage foam cells

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