Inhibition of Glutathione Production Induces Macrophage CD36 Expression and Enhances Cellular-oxidized Low Density Lipoprotein (oxLDL) Uptake

Yang, Xiaoxiao; Yao, Hui; Chen, Yuanli; Sun, Lei; Li, Yan; Ma, Xingzhe; Duan, Sheng‐Zhong; Li, Xiaoju; Xiang, Rong; Han, Jihong; Duan, Yajun

doi:10.1074/jbc.m115.654582

Cited by 51 publications

(33 citation statements)

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“…Determination of Cellular oxLDL Accumulation by Oil Red O Staining-After treatment, THP-1/PMA macrophages or peritoneal macrophages isolated from MacPpar␥ KO and Ppar␥ fl/fl mice in 24-well plates were incubated with rabbit anti-CD36 polyclonal antibody or normal rabbit IgG (0.3 g/sample) for 1 h. After normal IgG or anti-CD36 antibody was removed, cells were added with 50 g/ml of oxLDL and incubated for another 3 h. Cells were then fixed in 4% paraformaldehyde for 30 min, washed twice with PBS, and stained with Oil Red O solution (0.3% Oil Red O in 60% isopropyl alcohol) to determine cellular oxLDL accumulation as described (31). To determine cellular cholesteryl ester levels, after incubation with oxLDL as above described, cells in 10-cm plates were used to extract total cellular lipid followed by determination of cholesteryl esters with an assay kit (Wako Chemicals) as described (46).…”

Section: Methodsmentioning

confidence: 99%

“…Preparation of Plasmid DNA and Determination of CD36 Promoter Activity-The Ppar␥ expression vector (pEGFP-C2-PPAR␥) was generated as described (31). The human CD36 promoter (from Ϫ1186 to ϩ10) was constructed by PCR with human genomic DNA isolated from THP-1 monocytes and the following primers: forward, 5Ј-CCGCTCGAGCCTCTCCAG-TGACAGC-3Ј; reverse, 5Ј-CCCAAGCTTGTCACCTCCCG-TCATC-3Ј (the underlined letters represent the restriction sites for XhoI and HindIII, respectively).…”

Section: Methodsmentioning

confidence: 99%

“…6, C and D), the deficiency of PPAR␥ expression substantially reduced basal levels of CD36 expression and cellular lipid content, which implies it might be difficult to observe the further reduction of both by tamoxifen treatment, which is due to the sensitivity of detections. We previously reported that inhibition of cellular glutathione (GSH) production by inhibitor of glutamate-cysteine ligase (the rate-limiting enzyme for GSH production), L-buthionine-S,Rsulfoximine (BSO), activates macrophage CD36 expression and cellular oxLDL accumulation (31). Interestingly, the activation occurs at the translational level because BSO enhances CD36 translational efficiency (31).…”

Section: Tamoxifen and 4-hydroxytamoxifen Inhibit Cd36 Expression Bymentioning

confidence: 99%

“…We previously reported that inhibition of cellular glutathione (GSH) production by inhibitor of glutamate-cysteine ligase (the rate-limiting enzyme for GSH production), L-buthionine-S,Rsulfoximine (BSO), activates macrophage CD36 expression and cellular oxLDL accumulation (31). Interestingly, the activation occurs at the translational level because BSO enhances CD36 translational efficiency (31). To further confirm that tamoxifen inhibited CD36 expression and oxLDL accumulation in control were determined by Western blot analysis, respectively.…”

Section: Tamoxifen and 4-hydroxytamoxifen Inhibit Cd36 Expression Bymentioning

confidence: 99%

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Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Yu¹,

Jiang

Chen

et al. 2016

Journal of Biological Chemistry

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Macrophage CD36 binds and internalizes oxidized low density lipoprotein (oxLDL) to facilitate foam cell formation. CD36 expression is activated by peroxisome proliferator-activated receptor ␥ (PPAR␥). Tamoxifen, an anti-breast cancer medicine, has demonstrated pleiotropic functions including cardioprotection with unfully elucidated mechanisms. In this study, we determined that treatment of ApoE-deficient mice with tamoxifen reduced atherosclerosis, which was associated with decreased CD36 and PPAR␥ expression in lesion areas. At the cellular level, we observed that tamoxifen inhibited CD36 protein expression in human THP-1 monocytes, THP-1/PMA macrophages, and human blood monocyte-derived macrophages. Associated with decreased CD36 protein expression, tamoxifen reduced cellular oxLDL accumulation in a CD36-dependent manner. At the transcriptional level, tamoxifen decreased CD36 mRNA expression, promoter activity, and the binding of the PPAR␥ response element in CD36 promoter to PPAR␥ protein. Tamoxifen blocked ligand-induced PPAR␥ nuclear translocation and CD36 expression, but it increased PPAR␥ phosphorylation, which was due to that tamoxifen-activated ERK1/2. Furthermore, deficiency of PPAR␥ expression in macrophages abolished the inhibitory effect of tamoxifen on CD36 expression or cellular oxLDL accumulation both in vitro and in vivo. Taken together, our study demonstrates that tamoxifen inhibits CD36 expression and cellular oxLDL accumulation by inactivating the PPAR␥ signaling pathway, and the inhibition of macrophage CD36 expression can be attributed to the anti-atherogenic properties of tamoxifen.Tamoxifen (Nolvadex) and its immediate metabolite, 4-hydroxytamoxifen, belong to the class of drugs called selective estrogen receptor modulators (1). Dependent on target tissue/ molecules, tamoxifen can function either as an estrogen receptor (ER) 5 antagonist, such as in the mammary tissue, or as an ER agonist, such as in the endometrium (2). In the breast tissue, inactivation of ER by tamoxifen inhibits the growth of breast cancer cells. Therefore, tamoxifen is the most commonly used anti-hormonal drug for adjuvant treatment of patients with ERpositive breast cancer (2). In addition, tamoxifen has been determined to have a preventive function on breast cancer in the population of women with a high risk of developing this disease (3).Besides the effect on breast cancer, several lines of evidence have demonstrated the cardioprotective effects of tamoxifen. In animal models, tamoxifen reduces atherosclerosis in wild type mice and pro-atherogenic animal models, such as ApoE deficient (ApoE Ϫ/Ϫ ) mice and surgically postmenopausal monkeys (4 -6). In humans, tamoxifen lowers the incidence of fatal myocardial infarction, reduces the intima-media thickness of the common carotid artery in the postmenopausal women, and promotes the endothelium-dependent flow-mediated dilation in male patients with advanced atherosclerosis (7-9).Atherosclerosis is one of the major causes of coronary heart disease and a chronic patholo...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Tamoxifen and 4-hydroxytamoxifen Inhibit Cd36 Expression Bymentioning

confidence: 99%

Section: Tamoxifen and 4-hydroxytamoxifen Inhibit Cd36 Expression Bymentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Yu¹,

Jiang

Chen

et al. 2016

Journal of Biological Chemistry

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“…C57BL/6 wild-type mice were purchased from the Animal Center of Nanjing University (Nanjing, China). The specific macrophage PPAR␥-deficient (MPPAR␥ KO) mice and the corresponding control (PPAR␥ fl/fl ) mice were generated as described previously (45). To determine the effect of progesterone on CD36 expression in vivo, female PPAR␥ fl/fl mice and MPPAR␥ KO mice were intraperitoneally injected with vehicle (corn oil) or progesterone solution in corn oil (1 mg/mouse) for 4 consecutive days.…”

Section: Methodsmentioning

confidence: 99%

Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression

Yang¹,

Zhang²,

Chen

et al. 2016

Journal of Biological Chemistry

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Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPAR␥ expression and PPAR␥ promoter activity in a PRdependent manner and the binding of PR with the progesterone response element in the PPAR␥ promoter. Specific deletion of macrophage PPAR␥ (MPPAR␥ KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPAR␥ expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPAR␥ expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPAR␥-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy.Hormone replacement therapy (HRT, 4 estrogen plus progestin) is applied to postmenopausal women to alleviate or/and prevent common complications of female menopause. The initial use of estrogen alone as estrogen replacement therapy for postmenopausal women was reported to cause irregular bleeding and increase the risk of endometrial hyperplasia and carcinoma (1, 2). Later studies demonstrated that addition of a synthetic progesterone (for example, progestogen or progestin, which can demonstrate progestational effects similar to progesterone), can reduce the risk of estrogen-induced bleeding, endometrial hyperplasia, and carcinoma (3). Progesterone is a steroid hormone predominantly produced by the corpus luteum after ovulation and exerts its primary action by activating progesterone receptor (PR) (4).Compared with men at matched ages before menopause, women have much lower rates of cardiovascular disease, which can be attributed to endogenous estrogen production. Indeed, studies with animal models have confirmed the cardioprotective effects of estrogen. For example, treatment of ovariectomized rabbits or monkeys with estrogen reduces high-fat diet-induced atherosclerosis (5-7). However, both clinical observations and animal studies have demonstrated that addition of progestin in HRT attenuated the inhibitory effects of estrogen on atherosclerosis. Compared with placebo,...

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Supplementation with linoleic acid‐rich soybean oil stimulates macrophage foam cell formation via increased oxidative stress and diacylglycerol acyltransferase1‐mediated triglyceride biosynthesis

et al. 2016

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During the last decades there has been a staggering rise in human consumption of soybean oil (SO) and its major polyunsaturated fatty acid linoleic acid (LA). The role of SO or LA in cardiovascular diseases is highly controversial, and their impact on macrophage foam cell formation, the hallmark of early atherogenesis, is unclear. To investigate the effects of high SO or LA intake on macrophage lipid metabolism and the related mechanisms of action, C57BL/6 mice were orally supplemented with increasing levels of SO-based emulsion or equivalent levels of purified LA for 1 month, followed by analyses of lipid accumulation and peroxidation in aortas, serum and in peritoneal macrophages (MPM) of the mice. Lipid peroxidation and triglyceride mass in aortas from SO or LA supplemented mice were dose-dependently and significantly increased. In MPM from SO or LA supplemented mice, lipid peroxides were significantly increased and a marked accumulation of cellular triglycerides was found in accordance with enhanced triglyceride biosynthesis rate and overexpression of diacylglycerol acyltransferase1 (DGAT1), the key enzyme in triglyceride biosynthesis. In cultured J774A.1 macrophages treated with SO or LA, triglyceride accumulated via increased oxidative stress and a p38 mitogen-activated protein kinase (MAPK)-mediated overexpression of DGAT1. Accordingly, anti-oxidants (pomegranate polyphenols), inhibition of p38 MAPK (by SB202190) or DGAT1 (by oleanolic acid), all significantly attenuated SO or LA-induced macrophage triglyceride accumulation. These findings reveal novel mechanisms by which supplementation with SO or LA stimulate macrophage foam cell formation, suggesting a pro-atherogenic role for overconsumption of SO or LA. © 2016 BioFactors, 43(1):100-116, 2017.

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Inhibition of Glutathione Production Induces Macrophage CD36 Expression and Enhances Cellular-oxidized Low Density Lipoprotein (oxLDL) Uptake

Cited by 51 publications

References 50 publications

Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen

Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression

Supplementation with linoleic acid‐rich soybean oil stimulates macrophage foam cell formation via increased oxidative stress and diacylglycerol acyltransferase1‐mediated triglyceride biosynthesis

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