Role of baicalin in the treatment of mouse models of atherosclerosis and the underlying mechanism

doi:10.3969/j.issn.2095-4344.1187

Abstract

Abstract:

BACKGROUND: Modern laboratory and clinical studies have shown that baicalin can exert anti-atherosclerosis effect through multiple pathways, such as antioxidant stress, inhibition of proliferation and migration of vascular smooth muscle cells, but its mechanism is still unclear.
OBJECTIVE: To investigate the effect of baicalin on serum lipid, nitric oxide, nuclear factor kappa B, and its downstream inflammatory cytokines in mouse models of atherosclerosis.
METHODS: Sixty male ApoE-/- mice were randomized into five groups (n=10 per group). The control group was fed with normal diet, and the other five groups were fed with high-fat diet for 12 weeks to establish the atherosclerotic model. Subsequently, the control group and model group were given saline by gavage. The atorvastatin group was given atorvastatin 5 mg/(kg•d) by gavage. The baicalin group was given baicalin 50, 75, and 100 mg/(kg•d) by gavage. After 4 weeks of administration, blood lipid level was detected by automatic biochemical analyzer. Oil red O staining was used to observe development of the atherosclerotic plaques. Serum levels of inflammatory cytokines were detected by ELISA. The protein expression levels of nuclear factor kappa B p65 and vascular cell adhesion molecule-1 in aorta were detected by western blot assay. The level of nitric oxide was detected by nitrate reductase assay. The mRNA expression levels of nuclear factor kappa B p65, vascular cell adhesion molecule-1 and tumor necrosis factor alpha in aortic tissue were detected by real-time fluorescence quantitative PCR.
RESULTS AND CONCLUSION: (1) Compared with the control group, the total cholesterol, triacylglycerol and low-density lipoprotein levels were increased (P < 0.05), high-density lipoprotein cholesterol level was decreased (P < 0.05), the aortic intima thickness and plaques area were increased (P < 0.05), tumor necrosis factor alpha and interleukin 1 levels were increased (P < 0.05), nitric oxide level was decreased (P < 0.05), the protein expression of nuclear factor kappa B p65 and vascular cell adhesion molecule-1 was increased (P < 0.05), the mRNA expression levels of nuclear factor kappa B p65, vascular cell adhesion molecule-1 and tumor necrosis factor alpha were increased (P < 0.05) in the model group. (2) Compared with the model group, the lipid level in the atorvastatin and the low-, medium- and high-dose baicalin groups was improved significantly (P < 0.05), inflammatory factor levels were decreased (P < 0.05), nitric oxide level was increased (P < 0.05), the aortic intima thickness and plaques area were reduced, the protein expression of nuclear factor kappa B p65 and vascular cell adhesion molecule-1 was reduced (P < 0.05), and the mRNA expression levels of nuclear factor kappa B p65, vascular cell adhesion molecule-1 and tumor necrosis factor alpha were reduced (P < 0.05). The improvement of baicalin was in a dose-dependent manner. (3) Compared with the atorvastatin group, the expression levels of total cholesterol, interleukin 1 and vascular cell adhesion molecule-1 in the high-dose baicalin group were decreased (P < 0.05) and the level of nitric oxide was increased (P < 0.05). (4) These results show that baicalin may prevent the formation of atherosclerosis by improving blood lipid and suppressing the inflammatory pathway of nuclear factor kappa B.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: baicalin, atherosclerosis, nuclear factor kappa B, inflammatory cytokines, vascular cell adhesion molecule-1, tumor necrosis factor alpha

CLC Number:

R453.9
R313

Sun Zhizhong1, Jiang Yanjun1, Ji Shuliang1, Shi Chushuo1, Zhang Tian1, Zhou Xiaoqi1, Yang Zhihua1, Chen Yuexuan1, Luo Chuanjin2. Role of baicalin in the treatment of mouse models of atherosclerosis and the underlying mechanism[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(19): 3037-3043.

Figures/Tables 5

References

[1] 陈伟伟,高润霖,刘力生,等.《中国心血管病报告2017》概要[J].中国循环杂志,2018,33(1):1-8.

[2] Vanhoutte PM.Endothelial dysfunction: the first step toward coronary arteriosclerosis.Circ J.2009;73:595-601.

[3] Goff DC Jr,Lloyd-Jones DM,Bennett G,et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014;63(25 Pt B):2935-2959.

[4] Smith SC Jr,Benjamin EJ,Bonow RO,et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association.J Am Coll Cardiol. 2011;58(23):2432-2446.

[5] Chen CA,Wang TY,Varadharaj S,et al.S-glutathionylation uncouples eNOS and regulates its cellular and vascular function.Nature.2010;468(7327):1115-1118.

[6] 张芯,邢露茗,杨建飞,等.核因子-κB在动脉粥样硬化中的研究进展[J].现代生物医学进展,2015, 15(5):972-975.

[7] Liao P,Liu L,Wang B,et al.Baicalin and geniposide attenuate atherosclerosis involving lipids regulation and immunoregulation in ApoE-/- mice.Eur J Pharmacol.2014;740:488-495.

[8] Dong SJ,Zhong YQ,Lu WT,et al.Baicalin inhibits lipopolysaccharide-induced inflammation through signaling NF-kappaB pathway in HBE16 airway epithelial cells.Inflammation.2015;38:1493-1501.

[9] 星.ApoE-/-小鼠主动脉粥样硬化斑块中EMMPRIN和uPA的表达及阿托伐他汀干预的研究[D].重庆:第三军医大学,2012.

[10] Wu Y,Wang F,Fan L,et al.Baicalin alleviates atherosclerosis by relieving oxidative stress and inflammatory responses via inactivating the NF-κB and p38 MAPK signaling pathways.Biomed Pharmacother. 2018;97:1673-1679.

[11] 吕丽.基于PI3K/Akt/NF-κb信号通路槲皮素抗动脉粥样硬化作用研究[D].长春:吉林大学,2017.

[12] Yu XH,Zheng XL,Tang CK.Nuclear Factor-κB Activation as a Pathological Mechanism of Lipid Metabolism and Atherosclerosis.Adv Clin Chem.2015;70(3):1-30.

[13] Pant S,Deshmukh A,Gurumurthy GS,et al.Inflammation and atherosclerosis--revisited.J Cardiovasc Pharmacol Ther. 2014;19(2):170-178.

[14] Siragusa M,Fleming I.The eNOS signalosome and its link to endothelial dysfunction.Pflugers Arch.2016;468(7):1-13.

[15] Kanters E,Pasparakis M,Gijbels MJ,et al.Inhibition of NF-κB activation in macrophages increases atherosclerosis in LDL receptor–deficient mice. J Clin Invest.2003;112(8):1176-1185.

[16] Gareus R,Kotsaki E,Xanthoulea S,et al. Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis.Cell Metab.2008;8(5):372.

[17] Tornatore L,Thotakura AK,Bennett J,et al.The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation.Trends Cell Biol.2012;22(11):557-566.

[18] Zhang S,Reddick R,Piedrahita J,et al.Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.Science.1992;258(5081):468-471.

[19] 彭锐,吴伟,李荣,等.从P38-MARK信号通路研究黄芩苷对Ac-LDL+LPS诱导的与动脉粥样硬化相关巨噬细胞凋亡的影响[J].辽宁中医药大学学报,2016,18(4):29-32.

[20] 彭锐,潘华峰,吴伟,等.从SRA信号通路研究黄芩苷对Ac-LDL+LPS诱导的与动脉粥样硬化相关的巨噬细胞凋亡的影响[J].中华中医药杂志,2015,30(8):3014-3017.

[21] 彭锐,吴伟,余榕健,等.黄芩苷对AcLDL+LPS诱导的与动脉粥样硬化相关巨噬细胞凋亡的影响[J].中药新药与临床药理, 2014,25(4):432-427.

[22] Seo CS,Kim OS,Kim JH,et al.Simultaneous quantification and antiatherosclerosis effect of the traditional Korean medicine, Hwangryunhaedok-tang.BMC Complement Altern Med.2014;25(4):432-427.

[23] Kim OS,Seo CS,Kim Y,et al. Extracts of Scutellariae Radix inhibit low density lipoprotein oxidation and the lipopolysaccharide-included macrophage inflammatory response.Mol Med Rep.2015; 12(1):1335-1341.

[24] Wang B,Liao PP,Liu H,et al.Baicalin and geniposide inhibit the development of atherosclerosis by increasing Wnt1 and inhibiting dikkopf-related protein-1 expression.J Geriatr Cardiol.2016; 13(10):846-854.

[25] 张士聪,刘向群,陈焕芹,等.黄芩苷对高脂诱发小鼠动脉粥样硬化NF-κB及ACE2蛋白表达的影响[J].中国医院药学杂志, 2013,33(1):1-4.

[26] Liu L,Liao P,Wang B,et al.Oral administration of baicalin and geniposide induces regression of atherosclerosis via inhibiting dendritic cells in ApoE-knockout mice.Int Immunopharmacol.2014;20(1):197-204.