Inhibitory effects of resveratrol on foam cell formation are mediated through monocyte chemotactic protein-1 and lipid metabolism-related proteins

Dong,Wenpeng; Wang,Xianyue; Bi,Shenghui; Pan,Zhiguo; Liu,Shenxi; Yu,Hao; Lu,Hua; Lin,Xi; Wang,Xiaowu; Ma,Tao; Zhang,Weida

doi:10.3892/ijmm.2014.1680

Inhibitory effects of resveratrol on foam cell formation are mediated through monocyte chemotactic protein-1 and lipid metabolism-related proteins

Authors:
- Wenpeng Dong
- Xianyue Wang
- Shenghui Bi
- Zhiguo Pan
- Shenxi Liu
- Hao Yu
- Hua Lu
- Xi Lin
- Xiaowu Wang
- Tao Ma
- Weida Zhang
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Affiliations: Department of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China, Intensive Care Unit, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China, Information Center, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P.R. China
Published online on: February 28, 2014 https://doi.org/10.3892/ijmm.2014.1680
Pages: 1161-1168

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Abstract

Resveratrol has been shown to exert anti-atherosclerotic effects. 5' AMP-activated protein kinase (AMPK) and monocyte chemotactic protein-1 (MCP-1) play key roles in foam cell formation, which is considered as the initiation of atherosclerosis. Thus, in this study, we investigated whether resveratrol inhibits foam cell formation by regulating lipid accumulation and inflammation. For this purpose, THP-1 cells were treated with 100 nM phorbol 12-myristate 13-acetate (PMA) to induce their differentiation into macrophages. The macrophages were then pre-treated with 2.5 µM resveratrol and subsequently with serum-free (SF) medium alone or SF medium containing lipopolysaccharide (LPS; 100 ng/ml) and oxidized low-density lipoprotein (ox-LDL; 50 µg/ml) for 24 h to detect foam cell formation. To detect the expression of lipid accumulation-related proteins, the macrophages were treated with resveratrol. For the detection MCP-1 expression, the macrophages were treated with LPS and resveratrol, or with resveratrol alone. We incubated the THP-1-derived macrophages in resveratrol (2.5 µM) for 6 h in the presence or absence of 30 µM compound C for 4 h to detect the influence of compound C on the effects of resveratrol. The foam cells were examined using Red O staining. Gene expression levels were determined by qRT-PCR, western blot analysis and ELISA; lipid analysis was carried out by high-performance liquid chromatography (HPLC). The results revealed that resveratrol effectively suppressed foam cell formation induced by LPS. Resveratrol also suppressed lipid accumulation and downregulated the mRNA expression of peroxisome proliferator-activated receptor (PPAR)γ and PPARα, but had no effect on the expression of PPARβ/δ. Resveratrol also upregulated the expression of AMPK and Silent information regulator T1 (SIRT1). However, the effects of resveratrol on SIRT1, PPARγ and PPARα expression and lipid accumulation were reversed when the cells were pre-treated with compound C. Resveratrol downregulated the mRNA expression of MCP-1 in a dose-dependent manner and LPS upregulate its expression in a time-dependent manner. MCP-1 expression induced by LPS was inhibited by resveratrol at both the transcriptional and translational level. These data suggest that resveratrol inhibits foam cell formation by regulating the expression of MCP-1 and activating the AMPK-SIRT1-PPAR signaling pathway; thus, resveratrol may be a novel therapeutic agent for atherosclerosis.

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1	Andersson J, Libby P and Hansson GK: Adaptive immunity and atherosclerosis. Clin Immunol. 134:33–46. 2010. View Article : Google Scholar
2	Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 352:1685–1695. 2005. View Article : Google Scholar : PubMed/NCBI
3	Weber C, Zernecke A and Libby P: The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 8:802–815. 2008. View Article : Google Scholar : PubMed/NCBI
4	Boring L, Gosling J, Cleary M and Charo IF: Decreased lesion formation in CCR2^−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 394:894–897. 1998. View Article : Google Scholar : PubMed/NCBI
5	Gu L, Okada Y, Clinton SK, et al: Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 2:275–281. 1998. View Article : Google Scholar : PubMed/NCBI
6	Edfeldt K, Swedenborg J, Hansson GK and Yan ZQ: Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation. 105:1158–1161. 2002.PubMed/NCBI
7	Fan EG, Zhang LJ, Jiang S and Bai YH: Beneficial effects of resveratrol on atherosclerosis. J Med Food. 11:610–614. 2008. View Article : Google Scholar : PubMed/NCBI
8	Palmieri D, Pane B, Barisione C, et al: Resveratrol counteracts systemic and local inflammation involved in early abdominal aortic aneurysm development. J Surg Res. 171:e237–246. 2011. View Article : Google Scholar : PubMed/NCBI
9	Prasad K: Natural products in regression and slowing of progression of atherosclerosis. Curr Pharm Biotechnol. 11:794–800. 2010. View Article : Google Scholar : PubMed/NCBI
10	Zhu X, Liu Q, Wang M, et al: Activation of Sirt1 by resveratrol inhibits TNF-alpha induced inflammation in fibroblasts. PLoS ONE. 6:e270812011. View Article : Google Scholar : PubMed/NCBI
11	Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM and Scorei RI: Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition. 29:178–183. 2013. View Article : Google Scholar
12	Voloshyna I, Hai O, Littlefield MJ, Carsons S and Reiss AB: Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPAR gamma and adenosine. Eur J Pharmacol. 698:299–309. 2013. View Article : Google Scholar : PubMed/NCBI
13	Vingtdeux V, Chandakkar P, Zhao H, Davies P and Marambaud P: Small-molecule activators of AMP-activated protein kinase (AMPK), RSVA314 and RSVA405, inhibit adipogenesis. Mol Med. 17:1022–1030. 2011. View Article : Google Scholar : PubMed/NCBI
14	Fullerton MD, Steinberg GR and Schertzer JD: Immunometabolism of AMPK in insulin resistance and atherosclerosis. Mol Cell Endocrinol. 366:224–234. 2013. View Article : Google Scholar : PubMed/NCBI
15	Siriwardhana N, Kalupahana NS, Cekanova M, LeMieux M, Greer B and Moustaid-Moussa N: Modulation of adipose tissue inflammation by bioactive food compounds. J Nutr Biochem. 24:613–623. 2013. View Article : Google Scholar : PubMed/NCBI
16	Crandall JP and Barzilai N: Exploring the promise of resveratrol: where do we go from here? Diabetes. 62:1022–1023. 2013. View Article : Google Scholar : PubMed/NCBI
17	Coll B, Alonso-Villaverde C and Joven J: Monocyte chemoattractant protein-1 and atherosclerosis: is there room for an additional biomarker? Clin Chim Acta. 383:21–29. 2007. View Article : Google Scholar : PubMed/NCBI
18	Charo IF and Taubman MB: Chemokines in the pathogenesis of vascular disease. Circ Res. 95:858–866. 2004. View Article : Google Scholar : PubMed/NCBI
19	McLaren JE, Michael DR, Ashlin TG and Ramji DP: Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res. 50:331–347. 2011. View Article : Google Scholar : PubMed/NCBI
20	Kallio KA, Buhlin K, Jauhiainen M, et al: Lipopolysaccharide associates with pro-atherogenic lipoproteins in periodontitis patients. Innate Immun. 14:247–253. 2008. View Article : Google Scholar : PubMed/NCBI
21	Vink A, Schoneveld AH, van der Meer JJ, et al: In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation. 106:1985–1990. 2002. View Article : Google Scholar : PubMed/NCBI
22	Park D-W, Kim J-S, Chin B-R and Baek S-H: Resveratrol inhibits inflammation induced by heat-killed Listeria monocytogenes. J Med Food. 15:788–794. 2012. View Article : Google Scholar : PubMed/NCBI
23	Feng X, Zhang Y, Xu R, et al: Lipopolysaccharide up-regulates the expression of Fcalpha/mu receptor and promotes the binding of oxidized low-density lipoprotein and its IgM antibody complex to activated human macrophages. Atherosclerosis. 208:396–405. 2010. View Article : Google Scholar : PubMed/NCBI
24	Winnik S, Stein S and Matter CM: SIRT1 - an anti-inflammatory pathway at the crossroads between metabolic disease and atherosclerosis. Curr Vasc Pharmacol. 10:693–696. 2012. View Article : Google Scholar : PubMed/NCBI
25	Semple RK, Chatterjee VK and O’Rahilly S: PPAR gamma and human metabolic disease. J Clin Invest. 116:581–589. 2006. View Article : Google Scholar : PubMed/NCBI
26	dos Costa CS, Rohden F, Hammes TO, et al: Resveratrol upregulated SIRT1, FOXO1, and adiponectin and downregulated PPARgamma1–3 mRNA expression in human visceral adipocytes. Obes Surg. 21:356–361. 2011.PubMed/NCBI
27	Nimmagadda VK, Bever CT, Vattikunta NR, et al: Overexpression of SIRT1 protein in neurons protects against experimental autoimmune encephalomyelitis through activation of multiple SIRT1 targets. J Immunol. 190:4595–4607. 2013.
28	Cantó C, Jiang LQ, Deshmukh AS, et al: Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11:213–219. 2010.PubMed/NCBI
29	Hardie DG: AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 8:774–785. 2007. View Article : Google Scholar : PubMed/NCBI
30	Canto C, Gerhart-Hines Z, Feige JN, et al: AMPK regulates energy expenditure by modulating NAD⁺ metabolism and SIRT1 activity. Nature. 458:1056–1060. 2009. View Article : Google Scholar : PubMed/NCBI
31	Costford SR, Bajpeyi S, Pasarica M, et al: Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab. 298:E117–E126. 2010. View Article : Google Scholar : PubMed/NCBI
32	Libby P: Inflammation in atherosclerosis. Nature. 420:868–874. 2002. View Article : Google Scholar
33	Hansson GK and Libby P: The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 6:508–519. 2006. View Article : Google Scholar : PubMed/NCBI
34	Park D-W, Baek K, Kim J-R, et al: Resveratrol inhibits foam cell formation via NADPH oxidase 1-mediated reactive oxygen species and monocyte chemotactic protein-1. Exp Mol Med. 41:171–179. 2009. View Article : Google Scholar : PubMed/NCBI
35	Li H, Song Y, Li F, et al: Identification of lipid droplet-associated proteins in the formation of macrophage-derived foam cells using microarrays. Int J Mol Med. 26:231–239. 2010.PubMed/NCBI
36	Hou X, Xu S, Maitland-Toolan KA, et al: SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem. 283:20015–20026. 2008. View Article : Google Scholar : PubMed/NCBI
37	Lagouge M, Argmann C, Gerhart-Hines Z, et al: Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 127:1109–1122. 2006. View Article : Google Scholar : PubMed/NCBI
38	Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM and Puigserver P: Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 434:113–118. 2005. View Article : Google Scholar : PubMed/NCBI
39	Reverchon M, Cornuau M, Cloix L, et al: Visfatin is expressed in human granulosa cells: regulation by metformin through AMPK/SIRT1 pathways and its role in steroidogenesis. Mol Hum Reprod. 19:313–326. 2013. View Article : Google Scholar : PubMed/NCBI
40	Morita Y, Wada-Hiraike O, Yano T, et al: Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary. Reprod Biol Endocrinol. 10:142012. View Article : Google Scholar : PubMed/NCBI
41	Picard F, Kurtev M, Chung N, et al: Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 429:771–776. 2004. View Article : Google Scholar : PubMed/NCBI
42	Baur JA, Pearson KJ, Price NL, et al: Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 444:337–342. 2006. View Article : Google Scholar : PubMed/NCBI
43	von Grote EC, Venkatakrishnan V, Duo J and Stenken JA: Long-term subcutaneous microdialysis sampling and qRT-PCR of MCP-1, IL-6 and IL-10 in freely-moving rats. Mol Biosyst. 7:150–161. 2011.PubMed/NCBI
44	Wang J, Si Y, Wu C, et al: Lipopolysaccharide promotes lipid accumulation in human adventitial fibroblasts via TLR4-NF-kappaB pathway. Lipids Health Dis. 11:1392012. View Article : Google Scholar
45	Culpitt SV, Rogers DF, Fenwick PS, et al: Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax. 58:942–946. 2003. View Article : Google Scholar : PubMed/NCBI