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Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice

      Highlights

      • Dihydromyricetin (DMY) suppressed hepatic steatosis in LDLr−/− mice.
      • DMY inhibited atherosclerotic lesion formation in LDLr−/− mice.
      • DMY notably decreased oxidative stress and inflammatory reaction.
      • DMY inhibited injury, monocytes adhesion and oxidative stress in endothelial cells.
      • DMY inhibited macrophage foam cell formation and enhanced cholesterol efflux.

      Abstract

      Background and aims

      Dihydromyricetin, the most abundant flavonoid in Ampelopsis grossedentata, exerts numerous pharmacological activities, including anti-inflammatory, antioxidant, hepatoprotective, and lipid regulatory activities; however, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of dihydromyricetin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr−/−) mice.

      Methods

      Blood samples were collected for determination of serum lipid profiles, oxidized LDL (ox-LDL) and pro-inflammatory cytokines. Histology, hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation were performed on liver and aorta samples by molecular biology methods. The effects of dihydromyricetin on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) dysfunction and foam cell formation were further studied.

      Results

      (1) Dihydromyricetin ameliorated hyperlipidemia, reduced serum ox-LDL, IL-6 and TNF-α levels in HFD-fed LDLr−/− mice. Moreover, (2) dihydromyricetin suppressed hepatic lipid accumulation and increased protein expressions of PPARα, LXRα and ABCA1. (3) It inhibited atherosclerotic lesion formation and favoured features of plaque stability. (4) Dihydromyricetin prevented hepatic and aortic inflammation as evidenced by the reduced IL-6 and TNF-α mRNA expression; (5) it prevented hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in the liver and suppressing reactive oxygen species generation and NOX2 protein expression in both liver and aorta; (6) it inhibited oxLDL-induced injury, monocytes adhesion and oxidative stress in HUVECs and (7) inhibited macrophage foam cell formation and enhanced cholesterol efflux.

      Conclusions

      These findings suggest that dihydromyricetin could reduce atherosclerosis via its pleiotropic effects, including improvement of endothelial dysfunction, inhibition of macrophage foam cell formation, amelioration of lipid profiles, anti-inflammatory action and anti-oxidative effect.

      Keywords

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      References

        • Liu Z.
        • Xu S.
        • Huang X.
        • Wang J.
        • Gao S.
        • et al.
        Cryptotanshinone, an orally bioactive herbal compound from Danshen, attenuates atherosclerosis in apolipoprotein E-deficient mice: role of lectin-like oxidized LDL receptor-1 (LOX-1).
        Br. J. Pharmacol. 2015; 172: 5661-5675
        • Salvayre R.
        • Negre-Salvayre A.
        • Camaré C.
        Oxidative theory of atherosclerosis and antioxidants.
        Biochimie. 2016; 125: 281-296
        • Libby P.
        • Ridker P.M.
        • Hansson G.K.
        Progress and challenges in translating the biology of atherosclerosis.
        Nature. 2011; 473: 317-325
        • Zeller L.
        • Srivastave S.
        Macrophage functions in atherosclerosis.
        Circ. Res. 2014; 115: e83-e85
        • Xu Y.Y.
        • Du F.
        • Meng B.
        • Xie G.H.
        • Cao J.
        • et al.
        Hepatic overexpression of methionine sulfoxide reductase A reduces atherosclerosis in apolipoprotein E-deficient mice.
        J. Lipid. Res. 2015; 56: 1891-1900
        • Targher G.
        • Day C.P.
        • Bonora E.
        Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
        N. Engl. J. Med. 2010; 363: 1341-1350
        • Mulvihill E.E.
        • Huff M.W.
        Antiatherogenic properties of flavonoids: implications for cardiovascular health.
        Can. J. Cardiol. 2010; 26: 17A-21A
        • Le L.
        • Jiang B.
        • Wan W.
        • Zhai W.
        • Xu L.
        • et al.
        Metabolomics reveals the protective of Dihydromyricetin on glucose homeostasis by enhancing insulinsensitivity.
        Sci. Rep. 2016; 6: 36184
        • Wu Y.
        • Bai J.
        • Zhong K.
        • Huang Y.
        • Gao H.
        A dual antibacterial mechanism involved in membrane disruption and DNA binding of 2R,3R-dihydromyricetin from pine needles of Cedrus deodara against Staphylococcus aureus.
        Food. Chem. 2017; 218: 463-470
        • Ye L.
        • Wang H.
        • Duncan S.E.
        • Eigel W.N.
        • O'Keefe S.F.
        Antioxidant activities of Vine Tea (Ampelopsis grossedentata) extract and its major componentdihydromyricetin in soybean oil and cooked ground beef.
        Food. Chem. 2015; 172: 416-422
        • Tang N.
        • Ma J.
        • Wang K.S.
        • Mi C.
        • Lv Y.
        • et al.
        Dihydromyricetin suppresses TNF-α-induced NF-κB activation and target gene expression.
        Mol. Cell. Biochem. 2016; 422: 11-20
        • Xie J.
        • Liu J.
        • Chen T.M.
        • Lan Q.
        • Zhang Q.Y.
        Dihydromyricetin alleviates carbon tetrachloride-induced acute liver injury via JNK-dependent mechanism inmice.
        World. J. Gastroenterol. 2015; 21: 5473-5481
        • Yushan L.
        Effects of enshi-ampelopsis grossede on serum lipid and blood rheology and oxygen free radical of hyperlipidemia model rats.
        J. Hubei Inst. Natl.Med. Ed. 2006; 23: 7-9
        • Williams J.
        • Ensor C.
        • Gardner S.
        • Smith R.
        • Lodder R.
        BSN723T prevents atherosclerosis and weight gain in ApoE knockout mice fed a western diet.
        Webmedcentral. 2015; 6: 1-26
        • Chen S.
        • Zhao X.
        • Wan J.
        • Ran L.
        • Qin Y.
        • et al.
        Dihydromyricetin improves glucose and lipid metabolism and exerts anti-inflammatory effects innonalcoholic fatty liver disease: a randomized controlled trial.
        Pharmacol. Res. 2015; 99: 74-81
        • Yao W.
        • Huang C.
        • Sun Q.
        • Jing X.
        • Wang H.
        • et al.
        Tetrahydroxystilbene glucoside protects against oxidized LDL-induced endothelial dysfunction viaregulating vimentin cytoskeleton and its colocalization with ICAM-1 and VCAM-1.
        Cell. Physiol. Biochem. 2014; 34: 1442-1454
        • Kapourchali F.R.
        • Surendiran G.
        • Chen L.
        • Uitz E.
        • Bahadori B.
        • et al.
        Animal models of atherosclerosis.
        World. J. Clin. Cases. 2014; 2: 126-132
        • Nicholls S.J.
        • Pisaniello A.D.
        • Kataoka Y.
        • Puri R.
        Lipid pharmacotherapy for treatment of atherosclerosis.
        Expert. Opin. Pharmacother. 2014; 15: 1119-1125
        • Assini J.M.
        • Mulvihill E.E.
        • Sutherland B.G.
        • Telford D.E.
        • Sawyez C.G.
        • et al.
        Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr⁻/⁻ mice.
        J. Lipid.Res. 2013; 54: 711-724
        • Shen Y.
        • Ward N.C.
        • Hodgson J.M.
        • Puddey I.B.
        • Wang Y.
        • et al.
        Dietary quercetin attenuates oxidant-induced endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: a critical role for heme oxygenase-1.
        Free. Radic. Biol. Med. 2013; 65: 908-915
        • Guo S.
        • Tian H.
        • Dong R.
        • Yang N.
        • Zhang Y.
        • et al.
        Exogenous supplement of N-acetylneuraminic acid ameliorates atherosclerosis in apolipoprotein E-deficientmice.
        Atherosclerosis. 2016; 251: 183-191
        • Wouters K.
        • van Gorp P.J.
        • Bieghs V.
        • Gijbels M.J.
        • Duimel H.
        • et al.
        Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis.
        Hepatology. 2008; 48: 474-486
        • Teupser D.
        • Persky A.D.
        • Breslow J.L.
        Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptor-deficient C57BL/6J and FVB/NJ mice: comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement).
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1907-1913
        • Xie C.
        • Chen Z.
        • Zhang C.
        • Xu X.
        • Jin J.
        • et al.
        Dihydromyricetin ameliorates oleic acid-induced lipid accumulation in L02 and HepG2 cells by inhibitinglipogenesis and oxidative stress.
        Life. Sci. 2016; 157: 131-139
        • Cherkaoui-Malki M.
        • Surapureddi S.
        • El-Hajj H.I.
        • Vamecq J.
        • Andreoletti P.
        Hepatic steatosis and peroxisomal fatty acid beta-oxidation.
        Curr.Drug. Metab. 2012; 13: 1412-1421
        • Ji A.
        • Wroblewski J.M.
        • Cai L.
        • de Beer M.C.
        • Webb N.R.
        Nascent HDL formation in hepatocytes and role of ABCA1, ABCG1, and SR-BI.
        J. Lipid. Res. 2012; 53: 446-455
        • Ma Z.
        • Deng C.
        • Hu W.
        • Zhou J.
        • Fan C.
        • et al.
        Liver X receptors and their agonists: targeting for cholesterol homeostasis and cardiovascular diseases.
        Curr. Issues. Mol. Biol. 2016; 22: 41-64
        • Costet P.
        • Luo Y.
        • Wang N.
        Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor.
        J. Biol. Chem. 2000; 275: 28240-28245
        • Bobryshev Y.V.
        • Ivanova E.A.
        • Chistiakov D.A.
        • Nikiforov N.G.
        • Orekhov A.N.
        Macrophages and their role In atherosclerosis: pathophysiology and transcriptome analysis.
        Biomed. Res. Int. 2016; (2016): 9582430
        • Liu Z.
        • Wang J.
        • Huang X.
        • Li Z.
        • Liu P.
        Deletion of sirtuin 6 accelerates endothelial dysfunction and atherosclerosis in apolipoprotein E-deficientmice.
        Transl. Res. 2016; 172 (e2): 18-29
        • Pirillo A.
        • Norata G.D.
        • Catapano A.L.
        LOX-1, OxLDL, and atherosclerosis.
        Mediat. Inflamm. 2013; (2013): 152786
        • Yu X.H.
        • Zheng X.L.
        • Tang C.K.
        Nuclear factor-κB activation as a pathological mechanism of lipid metabolism and atherosclerosis.
        Adv. Clin. Chem. 2015; 70: 1-30
        • Basu S.
        Fatty acid oxidation and isoprostanes: oxidative strain and oxidative stress.
        Prostagl. Leukot. Essent. Fat. Acids. 2010; 82: 219-225
        • Loke W.M.
        • Proudfoot J.M.
        • Hodgson J.M.
        • McKinley A.J.
        • Hime N.
        • et al.
        Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction.
        Arterioscler. Thromb. Vasc. Biol. 2010; 30: 749-757
        • Wu F.
        • Li Y.
        • Song H.
        • Zhang Y.
        • Zhang Y.
        Preventive effect of dihydromyricetin against cisplatin-induced nephrotoxicity in vitro and in vivo.
        Evid. Based. Complement. Altern. Med. 2016; (2016): 7937385https://doi.org/10.1155/2016/7937385
        • Wang J.T.
        • Jiao P.
        • Zhou Y.
        • Liu Q.
        Protective effect of dihydromyricetin against lipopolysaccharide-induced acute kidney injury in a RatModel.
        Med. Sci. Monit. 2016; 22: 454-459
        • Liu S.
        • Ai Q.
        • Feng K.
        • Li Y.
        • Liu X.
        The cardioprotective effect of dihydromyricetin prevents ischemia-reperfusion-induced apoptosis in vivoand in vitro via the PI3K/Akt and HIF-1α signaling pathways.
        Apoptosis. 2016; 21: 1366-1385
        • Douglas G.
        • Bendall J.K.
        • Crabtree M.J.
        • Tatham A.L.
        • Carter E.E.
        Endothelial-specific Nox2 overexpression increases vascular superoxide and macrophage recruitment in ApoE-/- mice.
        Cardiovasc. Res. 2012; 94: 20-29
        • Judkins C.P.
        • Diep H.
        • Broughton B.R.S.
        • Mast A.E.
        • Hooker E.U.
        • et al.
        Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE-/- mice.
        Am. J. Physiol. Heart. Circ. Physiol. 2010; 298: H24-H32
        • Quesada I.M.
        • Lucero A.
        • Amaya C.
        • Meijles D.N.
        • Cifuentes M.E.
        Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques.
        Atherosclerosis. 2015; 242: 469-475
        • Del Ben M.
        • Polimeni L.
        • Carnevale R.
        • Bartimoccia S.
        • Nocella C.
        NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease.
        BMC. Gastroenterol. 2014; 14: 81
        • Wang Y.
        • Parlevliet E.T.
        • Geerling J.J.
        • van der Tuin S.J.
        • Zhang H.
        Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration.
        Br. J.Pharmacol. 2014; 171: 723-734
        • Kang J.H.
        • Rvu H.S.
        • Kim H.T.
        • Lee S.J.
        • Choi U.K.
        • et al.
        Proteomic analysis of human macrophages exposed to hypochlorite-oxidized low-densitylipoprotein.
        Biochim. Biophys. Acta. 2009; 1794: 446-458

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