Angiotensin‑(1‑7) stimulates cholesterol efflux from angiotensin II‑treated cholesterol‑loaded THP‑1 macrophages through the suppression of p38 and c‑Jun N‑terminal kinase signaling

Yang,Hui‑Yu; Bian,Yun‑Fei; Xiao,Chuan‑Shi; Liang,Bin; Zhang,Nana; Gao,Fen; Yang,Zhi‑Ming

doi:10.3892/mmr.2015.3484

Angiotensin‑(1‑7) stimulates cholesterol efflux from angiotensin II‑treated cholesterol‑loaded THP‑1 macrophages through the suppression of p38 and c‑Jun N‑terminal kinase signaling

Authors:
- Hui‑Yu Yang
- Yun‑Fei Bian
- Chuan‑Shi Xiao
- Bin Liang
- Nana Zhang
- Fen Gao
- Zhi‑Ming Yang
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Affiliations: Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China
Published online on: March 13, 2015 https://doi.org/10.3892/mmr.2015.3484
Pages: 1387-1392

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Abstract

Angiotensin II (Ang II) and Ang‑(1‑7) are key effector peptides of the renin‑angiotensin system. The present study aimed to investigate the effects of Ang‑(1‑7) on Ang II‑stimulated cholesterol efflux and the associated molecular mechanisms. Differentiated THP‑1 macrophages were treated with Ang II (1 µM) and/or Ang‑(1‑7) (10 and 100 nM) for 24 h and the cholesterol efflux and gene expression levels were assessed. Pharmacological inhibition of peroxisome proliferator‑activated receptor (PPAR)γ and mitogen‑activated protein kinases (MAPKs) were performed to identify the signaling pathways involved. The results demonstrated that Ang II significantly inhibited the cholesterol efflux from cholesterol‑loaded THP‑1 macrophages. Treatment with Ang‑(1‑7) led to a dose‑dependent restoration of cholesterol efflux in the Ang II‑treated cells. The co‑treatment with Ang‑(1‑7) and Ang II significantly increased the expression levels of adenosine triphosphate (ATP)‑binding cassette (ABC)A1 and ABCG1 compared with treatment with Ang II alone. This was coupled with increased expression levels of PPARγ and liver X receptor (LXR)α. The pharmacological inhibition of PPARγ significantly (P<0.05) eliminated the Ang‑(1‑7)‑mediated induction of ABCA1 and ABCG1 mRNA expression. Treatment with Ang‑(1‑7) caused the inactivation of c‑Jun N‑terminal kinases (JNK) and p38 MAPK signaling in the Ang II‑treated THP‑1 macrophages. In addition, the inhibition of JNK or p38 MAPK signaling using specific pharmacological inhibitors mimicked the Ang‑(1‑7)‑induced expression of PPARγ and LXRα. In conclusion, the data demonstrated that treatment with Ang‑(1‑7) promoted cholesterol efflux in Ang II‑treated THP‑1 macrophages, partly through inactivation of p38 and JNK signaling and by inducing the expression of PPARγ and LXRα. Ang (1‑7) may, therefore, have therapeutic benefits for the treatment of atherosclerosis.

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1	Libby P, Ridker PM and Maseri A: Inflammation and atherosclerosis. Circulation. 105:1135–1143. 2002. View Article : Google Scholar : PubMed/NCBI
2	Fenyo IM and Gafencu AV: The involvement of the monocytes/macrophages in chronic inflammation associated with atherosclerosis. Immunobiology. 218:1376–1384. 2013. View Article : Google Scholar : PubMed/NCBI
3	Yu XH, Fu YC, Zhang DW, Yin K and Tang CK: Foam cells in atherosclerosis. Clin Chim Acta. 424:245–252. 2013. View Article : Google Scholar : PubMed/NCBI
4	Yvan-Charvet L, Wang N and Tall AR: Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol. 30:139–143. 2010. View Article : Google Scholar :
5	Smith JD, Le Goff W, Settle M, Brubaker G, Waelde C, Horwitz A and Oda MN: ABCA1 mediates concurrent cholesterol and phospholipid efflux to apolipoprotein A-I. J Lipid Res. 45:635–644. 2004. View Article : Google Scholar : PubMed/NCBI
6	Matsuura F, Wang N, Chen W, Jiang XC and Tall AR: HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest. 116:1435–1442. 2006. View Article : Google Scholar : PubMed/NCBI
7	Costet P, Luo Y, Wang N and Tall AR: Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem. 275:28240–28245. 2000.PubMed/NCBI
8	Kennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N and Edwards PA: Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J Biol Chem. 276:39438–39447. 2001. View Article : Google Scholar : PubMed/NCBI
9	Chawla A, Boisvert WA, Lee CH, et al: A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 7:161–171. 2001. View Article : Google Scholar : PubMed/NCBI
10	Nagy ZS, Czimmerer Z and Nagy L: Nuclear receptor mediated mechanisms of macrophage cholesterol metabolism. Mol Cell Endocrinol. 368:85–98. 2013. View Article : Google Scholar
11	Wang Y, Tikellis C, Thomas MC and Golledge J: Angiotensin converting enzyme 2 and atherosclerosis. Atherosclerosis. 226:3–8. 2013. View Article : Google Scholar
12	Kawahito H, Yamada H, Irie D, et al: Periaortic adipose tissue-specific activation of the renin angiotensin system contributes to atherosclerosis development in uninephrectomized apoE−/− mice. Am J Physiol Heart Circ Physiol. 305:H667–H675. 2013. View Article : Google Scholar : PubMed/NCBI
13	Fujisaka T, Hoshiga M, Hotchi J, et al: Angiotensin II promotes aortic valve thickening independent of elevated blood pressure in apolipoprotein-E deficient mice. Atherosclerosis. 226:82–87. 2013. View Article : Google Scholar
14	Santos RA, Ferreira AJ, Verano-Braga T and Bader M: Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. J Endocrinol. 216:R1–R17. 2013. View Article : Google Scholar
15	Yang HY, Bian YF, Zhang HP, et al: Angiotensin-(1-7) treatment ameliorates angiotensin II-induced HUVEC apoptosis. Clin Exp Pharmacol Physiol. 39:1004–1010. 2012. View Article : Google Scholar : PubMed/NCBI
16	Yang JM, Dong M, Meng X, et al: Angiotensin-(1-7) dose-dependently inhibits atherosclerotic lesion formation and enhances plaque stability by targeting vascular cells. Arterioscler Thromb Vasc Biol. 33:1978–1985. 2013. View Article : Google Scholar : PubMed/NCBI
17	Takata Y, Chu V, Collins AR, et al: Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II. Circ Res. 97:e88–e96. 2005. View Article : Google Scholar : PubMed/NCBI
18	Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL and Touyz RM: Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 49:185–192. 2007. View Article : Google Scholar
19	Hwang JS, Kang ES, Ham SA, et al: Activation of peroxisome proliferator-activated receptor γ by rosiglitazone inhibits lipopolysaccharide-induced release of high mobility group box 1. Mediators Inflamm. 2012:3528072012. View Article : Google Scholar
20	Trasino SE, Kim YS and Wang TT: Ligand, receptor, and cell type-dependent regulation of ABCA1 and ABCG1 mRNA in prostate cancer epithelial cells. Mol Cancer Ther. 8:1934–1945. 2009. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
22	Rosenbaugh EG, Savalia KK, Manickam DS and Zimmerman MC: Antioxidant-based therapies for angiotensin II-associated cardiovascular diseases. Am J Physiol Regul Integr Comp Physiol. 304:R917–R928. 2013. View Article : Google Scholar : PubMed/NCBI
23	Kanome T, Watanabe T, Nishio K, Takahashi K, Hongo S and Miyazaki A: Angiotensin II upregulates acyl-CoA:cholesterol acyltransferase-1 via the angiotensin II Type 1 receptor in human monocyte-macrophages. Hypertens Res. 31:1801–1810. 2008. View Article : Google Scholar : PubMed/NCBI
24	Wang Y, Chen Z, Liao Y, et al: Angiotensin II increases the cholesterol content of foam cells via down-regulating the expression of ATP-binding cassette transporter A1. Biochem Biophys Res Commun. 353:650–654. 2007. View Article : Google Scholar : PubMed/NCBI
25	Mario EG, Santos SH, Ferreira AV, Bader M, Santos RA and Botion LM: Angiotensin-(1-7) Mas-receptor deficiency decreases peroxisome proliferator-activated receptor γ expression in adipocytes. Peptides. 33:174–177. 2012. View Article : Google Scholar
26	Dhaunsi GS, Yousif MH, Akhtar S, Chappell MC, Diz DI and Benter IF: Angiotensin-(1-7) prevents diabetes-induced attenuation in PPAR-gamma and catalase activities. Eur J Pharmacol. 638:108–114. 2010. View Article : Google Scholar : PubMed/NCBI
27	Ren J, Jin W and Chen H: oxHDL decreases the expression of CD36 on human macrophages through PPARgamma and p38 MAP kinase dependent mechanisms. Mol Cell Biochem. 342:171–181. 2010. View Article : Google Scholar : PubMed/NCBI
28	Rohde E, Schallmoser K, Reinisch A, et al: Pro-angiogenic induction of myeloid cells for therapeutic angiogenesis can induce mitogen-activated protein kinase p38-dependent foam cell formation. Cytotherapy. 13:503–512. 2011. View Article : Google Scholar :
29	Mei S, Gu H, Ward A, et al: p38 mitogen-activated protein kinase (MAPK) promotes cholesterol ester accumulation in macrophages through inhibition of macroautophagy. J Biol Chem. 287:11761–11768. 2012. View Article : Google Scholar : PubMed/NCBI
30	Min KJ, Um HJ, Cho KH and Kwon TK: Curcumin inhibits oxLDL-induced CD36 expression and foam cell formation through the inhibition of p38 MAPK phosphorylation. Food Chem Toxicol. 58:77–85. 2013. View Article : Google Scholar : PubMed/NCBI
31	Yin R, Dong YG and Li HL: PPARγ phosphorylation mediated by JNK MAPK: a potential role in macrophage-derived foam cell formation. Acta Pharmacol Sin. 27:1146–1152. 2006. View Article : Google Scholar : PubMed/NCBI
32	Santos SH, Andrade JM, Fernandes LR, et al: Oral Angiotensin-(1-7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet. Peptides. 46:47–52. 2013. View Article : Google Scholar : PubMed/NCBI
33	Moon JY, Tanimoto M, Gohda T, et al: Attenuating effect of angiotensin-(1-7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-A(y)/Ta mice. Am J Physiol Renal Physiol. 300:F1271–F1282. 2011. View Article : Google Scholar : PubMed/NCBI