Berberine combined with atorvastatin downregulates LOX‑1 expression through the ET‑1 receptor in monocyte/macrophages

  • Authors:
    • Liyi Chi
    • Lijing Peng
    • Xiaojing Hu
    • Na Pan
    • Yanhai Zhang
  • View Affiliations

  • Published online on: April 22, 2014     https://doi.org/10.3892/ijmm.2014.1748
  • Pages: 283-290
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Abstract

Studies have shown that the oxidative modification of low‑density lipoprotein (oxLDL) plays a major role in atherogenesis. Lectin‑like oxidized low‑density lipoprotein receptor‑1 (LOX‑1) mediated the transport of oxLDL into macrophages, which promoted foam cell formation. Targeting LOX‑1 may therefore be a promising approach to inhibit atherosclerosis. In the present study, we aimed to investigate the effect of berberine combined with atorvastatin on LOX‑1 and explore the underlying molecular mechanism involved. Expression of LOX‑1 in monocyte‑derived macrophages (MDMs) exposed to berberine (0, 0.1, 1, 10 and 100 nM) and atorvastatin (100 nM) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis. Results showed that the expression of LOX‑1 was decreased in a dose‑dependent manner. Additionally, knockdown of the endothelin‑1 (ET‑1) receptor significantly blocked the inhibitory effect of berberine on LOX‑1 expression. Body weight (BW), liver weight (LW) and kidney weight (KW) in the model rats were markedly increased at concentrations of berberine ≥1 µmol/kg, while heart weight (HW) and spleen weight (SW) remained constant among all groups. Berberine combined with atorvastatin also decreased serum total cholesterol (TC), triglyceride (TG) and low‑density lipoprotein‑cholesterol (LDL‑C) levels in the rat model as well as inflammation and oxidative stress. Furthermore, plasma ET‑1 levels and LOX‑1 expression were decreased by berberine combined with atorvastatin treatment, and the inhibitory effect on LOX‑1 was impeded by an ET‑1 receptor antagonist. The results demonstrated that berberine combined with atorvastatin downregulates LOX‑1 expression through ET‑1 receptors in monocyte/macrophages in vitro and in vivo.

References

1 

Lusis AJ: Atherosclerosis. Nature. 407:233–241. 2000. View Article : Google Scholar : PubMed/NCBI

2 

Li J, Chen CX and Shen YH: Effects of total glucosides from paeony (Paeonia lactiflora Pall) roots on experimental atherosclerosis in rats. J Ethnopharmacol. 135:469–475. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 352:1685–1695. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Pentikäinen MO, Oörni K, Ala-Korpela M and Kovanen PT: Modified LDL-trigger of atherosclerosis and inflammation in the arterial intima. J Intern Med. 247:359–370. 2000.PubMed/NCBI

5 

Plihtari R, Kovanen PT and Öörni K: Acidity increases the uptake of native LDL by human monocyte-derived macrophages. Atherosclerosis. 217:401–406. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Libby P, Ridker PM and Maseri A: Inflammation and atherosclerosis. Circulation. 105:1135–1143. 2002. View Article : Google Scholar

7 

Stein S, Lohmann C, Schäfer N, et al: SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis. Eur Heart J. 31:2301–2309. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Levitan I, Volkov S and Subbaiah PV: Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid Redox Signal. 13:39–75. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Kakutani M, Masaki T and Sawamura T: A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1. Proc Natl Acad Sci USA. 97:360–364. 2000. View Article : Google Scholar : PubMed/NCBI

10 

Chen M, Kakutani M, Naruko T, et al: Activation-dependent surface expression of LOX-1 in human platelets. Biochem Biophys Res Commun. 282:153–158. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Kataoka H, Kume N, Miyamoto S, et al: Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 21:955–960. 2001. View Article : Google Scholar : PubMed/NCBI

12 

Mitra S, Goyal T and Mehta JL: Oxidized LDL, LOX-1 and atherosclerosis. Cardiovasc Drugs Ther. 25:419–429. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Yamamoto N, Toyoda M, Abe M, et al: Lectin-like oxidized LDL receptor-1 (LOX-1) expression in the tubulointerstitial area likely plays an important role in human diabetic nephropathy. Intern Med. 48:189–194. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Nagase M, Hirose S, Sawamura T, Masaki T and Fujita T: Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats. Biochem Biophys Res Commun. 237:496–498. 1997. View Article : Google Scholar : PubMed/NCBI

15 

Rautureau Y and Schiffrin EL: Endothelin in hypertension: an update. Curr Opin Nephrol Hypertens. 21:128–136. 2012. View Article : Google Scholar

16 

Taguchi K and Hattori Y: Unlooked-for significance of cardiac versus vascular effects of endothelin-1 in the pathophysiology of pulmonary arterial hypertension. Circ Res. 112:227–229. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Watson AM, Li J, Schumacher C, et al: The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice. Diabetologia. 53:192–203. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Rodríguez-Pascual F, Busnadiego O, Lagares D and Lamas S: Role of endothelin in the cardiovascular system. Pharmacol Res. 63:463–472. 2011.

19 

Morawietz H, Rueckschloss U, Niemann B, et al: Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation. 100:899–902. 1999. View Article : Google Scholar : PubMed/NCBI

20 

Böhm F and Pernow J: The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 76:8–18. 2007.PubMed/NCBI

21 

Xu S, Liu Z, Huang Y, et al: Tanshinone II-A inhibits oxidized LDL-induced LOX-1 expression in macrophages by reducing intracellular superoxide radical generation and NF-κB activation. Transl Res. 160:114–124. 2012.PubMed/NCBI

22 

Kang B-Y, Khan JA, Ryu S, Shekhar R, Seung KB and Mehta JL: Curcumin reduces angiotensin II-mediated cardiomyocyte growth via LOX-1 inhibition. J Cardiovasc Pharmacol. 55:176–183. 2010.

23 

Guan S, Wang B, Li W, Guan J and Fang X: Effects of berberine on expression of LOX-1 and SR-BI in human macrophage-derived foam cells induced by ox-LDL. Am J Chin Med. 38:1161–1169. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Ou H-C, Song T-Y, Yeh Y-C, et al: EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling. J Appl Physiol (1985). 108:1745–1756. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Chang H-C, Chen T-G, Tai Y-T, Chen T-L, Chiu W-T and Chen R-M: Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J Cereb Blood Flow Metab. 31:842–854. 2011. View Article : Google Scholar

26 

Kuo C-L, Chi C-W and Liu T-Y: The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 203:127–137. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Brusq J-M, Ancellin N, Grondin P, et al: Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res. 47:1281–1288. 2006. View Article : Google Scholar : PubMed/NCBI

28 

Puato M, Faggin E, Rattazzi M, et al: Atorvastatin reduces macrophage accumulation in atherosclerotic plaques: a comparison of a nonstatin-based regimen in patients undergoing carotid endarterectomy. Stroke. 41:1163–1168. 2010. View Article : Google Scholar

29 

Zhou G, Ge S, Liu D, et al: Atorvastatin reduces plaque vulnerability in an atherosclerotic rabbit model by altering the 5-lipoxygenase pathway. Cardiology. 115:221–228. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Simmons G, McKnight À, Takeuchi Y, Hoshino H and Clapham PR: Cell-to-cell fusion, but not virus entry in macrophages by T-cell line tropic HIV-1 strains: a V3 loop-determined restriction. Virology. 209:696–700. 1995. View Article : Google Scholar : PubMed/NCBI

31 

McKnight Á, Griffiths DJ, Dittmar M, Clapham P and Thomas E: Characterization of a late entry event in the replication cycle of human immunodeficiency virus type 2. J Virol. 75:6914–6922. 2001.PubMed/NCBI

32 

Sitia S, Tomasoni L, Atzeni F, et al: From endothelial dysfunction to atherosclerosis. Autoimmun Rev. 9:830–834. 2010. View Article : Google Scholar

33 

Pawlak K, Mysliwiec M and Pawlak D: Oxidized LDL to autoantibodies against oxLDL ratio-the new biomarker associated with carotid atherosclerosis and cardiovascular complications in dialyzed patients. Atherosclerosis. 224:252–257. 2012. View Article : Google Scholar

34 

Howell KW, Meng X, Fullerton DA, Jin C, Reece TB and Cleveland JC Jr: Toll-like receptor 4 mediates oxidized LDL-induced macrophage differentiation to foam cells. J Surg Res. 171:e27–e31. 2011. View Article : Google Scholar : PubMed/NCBI

35 

Lu J, Mitra S, Wang X, Khaidakov M and Mehta JL: Oxidative stress and lectin-like ox-LDL-receptor LOX-1 in atherogenesis and tumorigenesis. Antioxid Redox Signal. 15:2301–2333. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Pandey H, Arjuman A, Roy KK and Chandra NC: Reciprocal coordination of a combination oral contraceptive containing desogestrel+ethinyl estradiol on the expression of LOX-1 and LDLR in placental trophoblast cells. Contraception. 84:e43–e49. 2011.PubMed/NCBI

37 

McMurray JJ, Holman RR, Haffner SM, et al; NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 362:1477–1490. 2010. View Article : Google Scholar : PubMed/NCBI

38 

Morawietz H, Duerrschmidt N, Niemann B, Galle J, Sawamura T and Holtz J: Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells. Biochem Biophys Res Commun. 284:961–965. 2001. View Article : Google Scholar : PubMed/NCBI

39 

Cani PD, Bibiloni R, Knauf C, et al: Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 57:1470–1481. 2008. View Article : Google Scholar : PubMed/NCBI

40 

Zhang X, Dong F, Ren J, Driscoll MJ and Culver B: High dietary fat induces NADPH oxidase-associated oxidative stress and inflammation in rat cerebral cortex. Exp Neurol. 191:318–325. 2005. View Article : Google Scholar : PubMed/NCBI

41 

Ju J, Liu Y, Hong J, Huang MT, Conney AH and Yang CS: Effects of green tea and high-fat diet on arachidonic acid metabolism and aberrant crypt foci formation in an azoxymethane-induced colon carcinogenesis mouse model. Nutr Cancer. 46:172–178. 2003. View Article : Google Scholar : PubMed/NCBI

42 

Lee JY, Sohn KH, Rhee SH and Hwang D: Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem. 276:16683–16689. 2001. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Chi, L., Peng, L., Hu, X., Pan, N., & Zhang, Y. (2014). Berberine combined with atorvastatin downregulates LOX‑1 expression through the ET‑1 receptor in monocyte/macrophages. International Journal of Molecular Medicine, 34, 283-290. https://doi.org/10.3892/ijmm.2014.1748
MLA
Chi, L., Peng, L., Hu, X., Pan, N., Zhang, Y."Berberine combined with atorvastatin downregulates LOX‑1 expression through the ET‑1 receptor in monocyte/macrophages". International Journal of Molecular Medicine 34.1 (2014): 283-290.
Chicago
Chi, L., Peng, L., Hu, X., Pan, N., Zhang, Y."Berberine combined with atorvastatin downregulates LOX‑1 expression through the ET‑1 receptor in monocyte/macrophages". International Journal of Molecular Medicine 34, no. 1 (2014): 283-290. https://doi.org/10.3892/ijmm.2014.1748