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Cardiovascular & Hematological Agents in Medicinal Chemistry

Author(s): Ruoyu Wu, Linqi Zhang, Hongjun Xu, Hongxu Chen, Wei Zhao, Yongjie Zhou, Luyang Zhou, Jiangli Wu* and Shengjun An*

DOI: 10.2174/1871525721666230206112134

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Salvia miltiorrhiza Extract Prevents the Occurrence of Early Atherosclerosis in Apoe -/- Mice via TLR4/ NF-kB Pathway

Page: [232 - 239] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Objective: Salvia miltiorrhiza (SM) contains four major aqueous active ingredients, which have been isolated, purified and identified as danshensu (DSS), salvianolic acid A (Sal-A), salvianolic acid B (Sal-B) and protocatechuic aldehyde (PAL), A mixture of these four ingredients is called SABP. Although aqueous extract from Salvia miltiorrhiza has been traditionally used to treat cardiovascular diseases, the efficacy and function of the optimal ratio of SABP in preventing and treating cardiovascular diseases remain unknown. This study aims to explore the antiinflammatory mechanisms underlying the attenuation of atherosclerosis development by aqueous extract from Salvia miltiorrhiza.

Methods: Male ApoE-/- mice (6 weeks) were randomly allocated into three groups: the model group (Model), the SABP group (SABP), and the rosuvastatin calcium group (RC). Male C57BL/6 mice (6 weeks) were used as a control group. All mice were fed with an ordinary diet. After 8 weeks of treatment, the lipid profiles in serum and the lactate dehydrogenase (LDH) and creatine kinase (CK) in heart tissue were measured using an automatic biochemical analyzer. Alterations of the thoracic aorta and the heart were assessed using Hematoxylin and eosin staining. The protein expression of Toll-like receptor 4 (TLR4), TGF beta-activated kinase 1 (TAK1), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the heart tissue were determined though immunohistochemistry and western blotting analysis.

Results: The serum low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) levels were increased, and the high-density lipoprotein cholesterol (HDL-C) level was decreased in ApoE-/- mice. SABP significantly decreased serum lipid levels and improved histopathology in the thoracic aorta. In addition. SABP treatment inhibited the expression of TLR4, TAK1, NF-κB, IL-6 and TNF-α in the heart in ApoE-/- mice. The LDH and CK in the heart did not differ significantly among different groups, and the heart did not have obvious pathological changes.

Conclusion: These findings indicated that SABP may exert an anti-atherosclerotic effect by lowering blood lipids and inhibiting inflammatory response via TLR4/ NF-κB signaling pathway.

Graphical Abstract

[1]
Libby, P. Inflammation in atherosclerosis. Nature, 2002, 420(6917), 868-874.
[http://dx.doi.org/10.1038/nature01323] [PMID: 12490960]
[2]
Greaves, D.; Channon, K. Inflammation and immune responses in atherosclerosis. Trends Immunol., 2002, 23(11), 535-541.
[http://dx.doi.org/10.1016/S1471-4906(02)02331-1] [PMID: 12401406]
[3]
Cole, J.E.; Georgiou, E.; Monaco, C. The expression and functions of toll-like receptors in atherosclerosis. Mediators Inflamm., 2010, 2010, 1-18.
[http://dx.doi.org/10.1155/2010/393946] [PMID: 20652007]
[4]
Xing, S.; Zheng, F.; Zhang, W.; Wang, D.; Xing, Q. Relationship between toll-like receptor 4 levels in aorta and severity of atherosclerosis. J. Int. Med. Res., 2014, 42(4), 958-965.
[http://dx.doi.org/10.1177/0300060514534645] [PMID: 24925583]
[5]
Bowman, J.D.; Surani, S.; Horseman, M.A. Endotoxin, toll-like Receptor-4, and atherosclerotic heart disease. Curr. Cardiol. Rev., 2017, 13(2), 86-93.
[PMID: 27586023]
[6]
den Dekker, W.K.; Cheng, C.; Pasterkamp, G.; Duckers, H.J. Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis, 2010, 209(2), 314-320.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.09.075] [PMID: 19900676]
[7]
Il Jang, S.; Jin Kim, H.; Kim, Y.J.; Jeong, S.I.; You, Y.O. Tanshinone IIA inhibits LPS-induced NF-κB activation in RAW 264.7 cells: Possible involvement of the NIK–IKK, ERK1/2, p38 and JNK pathways. Eur. J. Pharmacol., 2006, 542(1-3), 1-7.
[http://dx.doi.org/10.1016/j.ejphar.2006.04.044] [PMID: 16797002]
[8]
Nizamutdinova, I.T.; Kim, Y.M.; Jin, H.; Son, K.H.; Lee, J.H.; Chang, K.C.; Kim, H.J. Tanshinone IIA inhibits TNF-α-mediated induction of VCAM-1 but not ICAM-1 through the regulation of GATA-6 and IRF-1. Int. Immunopharmacol., 2012, 14(4), 650-657.
[http://dx.doi.org/10.1016/j.intimp.2012.09.017] [PMID: 23085565]
[9]
Cockerill, G.W.; Huehns, T.Y.; Weerasinghe, A.; Stocker, C.; Lerch, P.G.; Miller, N.E.; Haskard, D.O. Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation. Circulation, 2001, 103(1), 108-112.
[http://dx.doi.org/10.1161/01.CIR.103.1.108] [PMID: 11136694]
[10]
Su, P.; Tong, Y.; Cheng, Q.; Hu, Y.; Zhang, M.; Yang, J.; Teng, Z.; Gao, W.; Huang, L. Functional characterization of ent-copalyl diphosphate synthase, kaurene synthase and kaurene oxidase in the Salvia miltiorrhiza gibberellin biosynthetic pathway. Sci. Rep., 2016, 6(1), 23057.
[http://dx.doi.org/10.1038/srep23057] [PMID: 26971881]
[11]
Zhang, T.; Xu, J.; Li, D.; Chen, J.; Shen, X.; Xu, F.; Teng, F.; Deng, Y.; Ma, H.; Zhang, L.; Zhang, G.; Zhang, Z.; Wu, W.; Liu, X.; Yang, M.; Jiang, B.; Guo, D. Salvianolic acid A, a matrix metalloproteinase-9 inhibitor of Salvia miltiorrhiza, attenuates aortic aneurysm formation in apolipoprotein E-deficient mice. Phytomedicine, 2014, 21(10), 1137-1145.
[http://dx.doi.org/10.1016/j.phymed.2014.05.003] [PMID: 24916705]
[12]
Wu, C.; Chen, W.; Ding, H.; Li, D.; Wen, G.; Zhang, C.; Lu, W.; Chen, M.; Yang, Y. Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3 at linker regions in vivo and in vitro. Life Sci., 2019, 239, 116881.
[http://dx.doi.org/10.1016/j.lfs.2019.116881] [PMID: 31678285]
[13]
Bao, Y.; Wang, L.; Xu, Y.; Yang, Y.; Wang, L.; Si, S.; Cho, S.; Hong, B. Salvianolic acid B inhibits macrophage uptake of modified low density lipoprotein (mLDL) in a scavenger receptor CD36-dependent manner. Atherosclerosis, 2012, 223(1), 152-159.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.05.006] [PMID: 22658257]
[14]
Tang, Y.; Wang, M.; Chen, C.; Le, X.; Sun, S.; Yin, Y. Cardiovascular protection with danshensu in spontaneously hypertensive rats. Biol. Pharm. Bull., 2011, 34(10), 1596-1601.
[http://dx.doi.org/10.1248/bpb.34.1596] [PMID: 21963501]
[15]
Jiang, B.; Li, D.; Deng, Y.; Teng, F.; Chen, J.; Xue, S.; Kong, X.; Luo, C.; Shen, X.; Jiang, H.; Xu, F.; Yang, W.; Yin, J.; Wang, Y.; Chen, H.; Wu, W.; Liu, X.; Guo, D. Salvianolic acid A, a novel matrix metalloproteinase-9 inhibitor, prevents cardiac remodeling in spontaneously hypertensive rats. PLoS One, 2013, 8(3), e59621.
[http://dx.doi.org/10.1371/journal.pone.0059621] [PMID: 23533637]
[16]
Fang, X.; Liu, Y.; Lu, J.; Hong, H.; Yuan, J.; Zhang, Y.; Wang, P.; Liu, P.; Ye, J. Protocatechuic aldehyde protects against isoproterenol-induced cardiac hypertrophy via inhibition of the JAK2/STAT3 signaling pathway. Naunyn. Schmiedebergs Arch1. Pharmacol., 2018, 391, 1373-1385.
[17]
Zhou, Y.; Sun, W.; Chen, J.; Tan, H.; Xiao, Y.; Li, Q.; Ji, Q.; Gao, S.; Chen, L.; Chen, S.; Zhang, L.; Chen, W. SmMYC2a and SmMYC2b played similar but irreplaceable roles in regulating the biosynthesis of tanshinones and phenolic acids in Salvia miltiorrhiza. Sci. Rep., 2016, 6(1), 22852.
[http://dx.doi.org/10.1038/srep22852] [PMID: 26947390]
[18]
Lin, C.; Liu, Z.; Lu, Y.; Yao, Y.; Zhang, Y.; Ma, Z.; Kuai, M.; Sun, X.; Sun, S.; Jing, Y.; Yu, L.; Li, Y.; Zhang, Q.; Bian, H. Cardioprotective effect of Salvianolic acid B on acute myocardial infarction by promoting autophagy and neovascularization and inhibiting apoptosis. J. Pharm. Pharmacol., 2016, 68(7), 941-952.
[http://dx.doi.org/10.1111/jphp.12567] [PMID: 27139338]
[19]
Zhang, J.; An, S.J.; Fu, J.Q.; Liu, P.; Shao, T.M.; Li, M.; Li, X.; Jiao, Z.; Chai, X.Q. Mixed aqueous extract of Salvia Miltiorrhiza reduces blood pressure through inhibition of vascular remodelling and oxidative stress in spontaneously hypertensive rats. Cell. Physiol. Biochem., 2016, 40(1-2), 347-360.
[http://dx.doi.org/10.1159/000452550] [PMID: 27866193]
[20]
Chen, Z.; Gao, X.; Jiao, Y.; Qiu, Y.; Wang, A.; Yu, M.; Che, F.; Li, S.; Liu, J.; Li, J.; Zhang, H.; Yu, C.; Li, G.; Gao, Y.; Pan, L.; Sun, W.; Guo, J.; Cao, B.; Zhu, Y.; Xu, H. Tanshinone IIA exerts anti-inflammatory and immune-regulating effects on vulnerable atherosclerotic plaque partially via the TLR4/MyD88/NF-κB signal pathway. Front. Pharmacol., 2019, 10, 850.
[http://dx.doi.org/10.3389/fphar.2019.00850] [PMID: 31402870]
[21]
Tian, F.; Zhang, K.; Kang, A.; Zhou, R.; Zhou, S.; Zheng, Z.; Zhao, D. Characteristics of heart, liver and kidney lesions in 12-month-old ApoE-/- atherosclerosis mice. Zhongguo Laonianxue Zazhi, 2010, 30, 190-192.
[22]
Shapiro, M.D.; Fazio, S. From lipids to inflammation: New approaches to reducing atherosclerotic risk. Circ. Res., 2016, 118(4), 732-749.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306471] [PMID: 26892970]
[23]
Zhou, Q.; Liao, J.K. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ. J., 2010, 74(5), 818-826.
[http://dx.doi.org/10.1253/circj.CJ-10-0110] [PMID: 20424337]
[24]
Zadelaar, S.; Kleemann, R.; Verschuren, L.; de Vries-Van der Weij, J.; van der Hoorn, J.; Princen, H.M.; Kooistra, T. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler. Thromb. Vasc. Biol., 2007, 27(8), 1706-1721.
[http://dx.doi.org/10.1161/ATVBAHA.107.142570] [PMID: 17541027]
[25]
Song, K.; Hou, Y.H.; Su, D.N.; Yang, H.; Bai, Y.X.; Li, H.; Lou, L.X.; Zhao, Y.Z.; Wu, A.M.; Tu, Y.; Nie, B. Effect of Simiao Yongan decoction on IL-6 and MCP-1 in Apo E-/- atherosclerotic Mice. Zhongguo Xiandai Zhongyao, 2019, 21, 441-447. [J].
[26]
Yang, L.X.; Heng, X.H.; Guo, R.W.; Si, Y.K.; Qi, F.; Zhou, X.B. Atorvastatin inhibits the 5-lipoxygenase pathway and expression of CCL3 to alleviate atherosclerotic lesions in atherosclerotic ApoE knockout mice. J. Cardiovasc. Pharmacol., 2013, 62(2), 205-211.
[http://dx.doi.org/10.1097/FJC.0b013e3182967fc0] [PMID: 23615158]
[27]
Feng, J.; Guo, C.; Zhu, Y.; Pang, L.; Yang, Z.; Zou, Y.; Zheng, X. Baicalin down regulates the expression of TLR4 and NFkB-p65 in colon tissue in mice with colitis induced by dextran sulfate sodium. Int. J. Clin. Exp. Med., 2014, 7(11), 4063-4072.
[PMID: 25550915]
[28]
Fei, X.; Chen, C.; Kai, S.; Fu, X.; Man, W.; Ding, B.; Wang, C.; Xu, R. Eupatilin attenuates the inflammatory response induced by intracerebral hemorrhage through the TLR4/MyD88 pathway. Int. Immunopharmacol., 2019, 76, 105837.
[http://dx.doi.org/10.1016/j.intimp.2019.105837] [PMID: 31476693]
[29]
Shinohara, M.; Hirata, K.; Yamashita, T.; Takaya, T.; Sasaki, N.; Shiraki, R.; Ueyama, T.; Emoto, N.; Inoue, N.; Yokoyama, M.; Kawashima, S. Local overexpression of toll-like receptors at the vessel wall induces atherosclerotic lesion formation: synergism of TLR2 and TLR4. Arterioscler. Thromb. Vasc. Biol., 2007, 27(11), 2384-2391.
[http://dx.doi.org/10.1161/ATVBAHA.106.139253] [PMID: 17872459]
[30]
Ha, S.J.; Lee, J.; Song, K.M.; Kim, Y.H.; Lee, N.H.; Kim, Y.E.; Jung, S.K. Ultrasonicated Lespedeza cuneata extract prevents TNF-α-induced early atherosclerosis in vitro and in vivo. Food Funct., 2018, 9(4), 2090-2101.
[http://dx.doi.org/10.1039/C7FO01666B] [PMID: 29611586]
[31]
Bohannon, J.K.; Hernandez, A.; Enkhbaatar, P.; Adams, W.L.; Sherwood, E.R. The immunobiology of toll-like receptor 4 agonists: From endotoxin tolerance to immunoadjuvants. Shock, 2013, 40(6), 451-462.
[http://dx.doi.org/10.1097/SHK.0000000000000042] [PMID: 23989337]
[32]
Baeuerle, P.A.; Baltimore, D. I kappa B: A specific inhibitor of the NF-kappa B transcription factor. Science, 1988, 242(4878), 540-546.
[http://dx.doi.org/10.1126/science.3140380] [PMID: 3140380]