Combinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput Screening1386-20731875-5402Bentham Science64369610.2174/1386207326666230703150803ChemistryResearch ArticleExploring the Mechanism of Si-miao-yong-an Decoction in the Treatment of Coronary Heart Disease based on Network Pharmacology and Experimental VerificationZhangJingmeiinfo@benthamscience.netXueSiminginfo@benthamscience.netChenHuaninfo@benthamscience.netJiangHaixuinfo@benthamscience.netGaoPengronginfo@benthamscience.netLuLinghuiinfo@benthamscience.netWangQiyaninfo@benthamscience.netSchool of Life Sciences, Beijing University of Chinese MedicineSchool of Chinese Materia, Beijing University of Chinese MedicineSchool of Traditional Chinese Medicine,, Beijing University of Chinese MedicineSchool of Traditional Chinese Medicine, Beijing University of Chinese Medicine01012024271576807012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjpbr.com/1386-2073/article/view/643696

Background:To investigate the active ingredients and the mechanisms of Si-miaoyong- an Decoction (SMYA) in the treatment of coronary heart disease (CHD) by using network pharmacology, molecular docking technology, and in vitro validation.

Methods:Through the Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), Uniprot database, GeneCards database, and DAVID database, we explored the core compounds, core targets and signal pathways of the effective compounds of SMYA in the treatment of CHD. Molecular docking technology was applied to evaluate the interactions between active compounds and key targets. The hypoxia-reoxygenation H9C2 cell model was applied to carry out in vitro verification experiments. A total of 109 active ingredients and 242 potential targets were screened from SMYA. A total of 1491 CHD-related targets were retrieved through the Gene- Cards database and 155 overlapping CHD-related SMYA targets were obtained. PPI network topology analysis indicated that the core targets of SMYA in the treatment of CHD include interleukin- 6 (IL-6), tumor suppressor gene (TP53), tumor necrosis factor (TNF), vascular endothelial growth factor A (VEGFA), phosphorylated protein kinase (AKT1) and mitogen-activated protein kinase (MAPK). KEGG enrichment analysis demonstrated that SMYA could regulate Pathways in cancer, phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway, hypoxiainducible factor-1(HIF-1) signaling pathway, VEGF signaling pathway, etc.

Results:Molecular docking showed that quercetin had a significant binding activity with VEGFA and AKT1. In vitro studies verified that quercetin, the major effective component of SMYA, has a protective effect on the cell injury model of cardiomyocytes, partially by up-regulating expressions of phosphorylated AKT1 and VEGFA.

Conclusion:SMYA has multiple components and treats CHD by acting on multiple targets. Quercetin is one of its key ingredients and may protect against CHD by regulating AKT/VEGFA pathway.

Si-miao-yong-an decoctionnetwork pharmacologycoronary heart diseasemolecular dockingexperimental verificationheart diseaseTCMSP.Wirtz, P.H.; von Känel, R. Psychological stress, inflammation, and coronary heart disease. Curr. Cardiol. Rep., 2017, 19(11), 111. doi: 10.1007/s11886-017-0919-x PMID: 28932967Townsend, N.; Nichols, M.; Scarborough, P.; Rayner, M. Cardiovascular disease in Europe — epidemiological update 2015. Eur. Heart J., 2015, 36(40), 2696-2705. doi: 10.1093/eurheartj/ehv428 PMID: 26306399Arenas de Larriva, A.P.; Limia-Pérez, L.; Alcalá-Díaz, J.F.; Alonso, A.; López-Miranda, J.; Delgado-Lista, J. Ceruloplasmin and coronary heart disease—A systematic review. Nutrients, 2020, 12(10), 3219. doi: 10.3390/nu12103219 PMID: 33096845Ren, Y.; Chen, X.; Li, P.; Zhang, H.; Su, C.; Zeng, Z.; Wu, Y.; Xie, X.; Wang, Q.; Han, J.; Guo, S.; Liu, B.; Wang, W. Si-Miao-Yong-An decoction ameliorates cardiac function through restoring the equilibrium of SOD and NOX2 in heart failure mice. Pharmacol. Res., 2019, 146, 104318. doi: 10.1016/j.phrs.2019.104318 PMID: 31228552Su, C.; Wang, Q.; Zhang, H.; Jiao, W.; Luo, H.; Li, L.; Chen, X.; Liu, B.; Yu, X.; Li, S.; Wang, W.; Guo, S. Si-Miao-Yong-An decoction protects against cardiac hypertrophy and dysfunction by inhibiting platelet aggregation and activation. Front. Pharmacol., 2019, 10, 990. doi: 10.3389/fphar.2019.00990 PMID: 31619988Zhao, Y.; Jiang, Y.; Chen, Y.; Zhang, F.; Zhang, X.; Zhu, L.; Yao, X. Dissection of mechanisms of Chinese medicinal formula Si-Miao-Yong-an decoction protects against cardiac hypertrophy and fibrosis in isoprenaline-induced heart failure. J. Ethnopharmacol., 2020, 248, 112050. doi: 10.1016/j.jep.2019.112050 PMID: 31265887Qi, Z.; Li, M.; Zhu, K. Si-Miao-Yong-An on promoting the maturation of Vasa Vasorum and stabilizing atherosclerotic plaque in ApoE(-/-) mice: An experimental study. Biomedicine & p. Pharmacotherapy,, 2019, 114, 108785.Peng, L.; Li, M.; Xu, Y.; Zhang, G.; Yang, C.; Zhou, Y.; Li, L.; Zhang, J. Effect of Si-Miao-Yong-An on the stability of atherosclerotic plaque in a diet-induced rabbit model. J. Ethnopharmacol., 2012, 143(1), 241-248. doi: 10.1016/j.jep.2012.06.030 PMID: 22750436Yan, S.K.; Liu, R.H.; Jin, H.Z.; Liu, X.R.; Ye, J.; Shan, L.; Zhang, W.D. "Omics" in pharmaceutical research: Overview, applications, challenges, and future perspectives. Chin. J. Nat. Med., 2015, 13(1), 3-21. doi: 10.1016/S1875-5364(15)60002-4 PMID: 25660284Lima, A.M.; Siqueira, A.S.; Möller, M.L.S.; Souza, R.C.; Cruz, J.N.; Lima, A.R.J.; Silva, R.C.; Aguiar, D.C.F.; Junior, J.L.S.G.V.; Gonçalves, E.C. In silico improvement of the cyanobacterial lectin microvirin and mannose interaction. J. Biomol. Struct. Dyn., 2022, 40(3), 1064-1073. doi: 10.1080/07391102.2020.1821782 PMID: 32990187Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6(1), 13. doi: 10.1186/1758-2946-6-13 PMID: 24735618Tao, W.; Xu, X.; Wang, X.; Li, B.; Wang, Y.; Li, Y.; Yang, L. Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. J. Ethnopharmacol., 2013, 145(1), 1-10. doi: 10.1016/j.jep.2012.09.051 PMID: 23142198Xu, X.; Zhang, W.; Huang, C.; Li, Y.; Yu, H.; Wang, Y.; Duan, J.; Ling, Y. A novel chemometric method for the prediction of human oral bioavailability. Int. J. Mol. Sci., 2012, 13(6), 6964-6982. doi: 10.3390/ijms13066964 PMID: 22837674UniProt. A hub for protein information. Nucleic Acids Res., 2015, 43(Database issue), D204-D212. PMID: 25348405Wang, N.; Zhu, F.; Shen, M.; Qiu, L.; Tang, M.; Xia, H.; Chen, L.; Yuan, Y.; Ma, S.; Chen, K. Network pharmacology-based analysis on bioactive anti-diabetic compounds in Potentilla discolor bunge. J. Ethnopharmacol., 2019, 241, 111905. doi: 10.1016/j.jep.2019.111905 PMID: 31022565Eberhardt, J.; Santos-Martins, D.; Tillack, A.F.; Forli, S. AutoDock vina 1.2.0: New Docking methods, expanded force field, and python bindings. J. Chem. Inf. Model., 2021, 61(8), 3891-3898. doi: 10.1021/acs.jcim.1c00203 PMID: 34278794Almeida, V.M.; Dias, Ê.R.; Souza, B.C.; Cruz, J.N.; Santos, C.B.R.; Leite, F.H.A.; Queiroz, R.F.; Branco, A. Methoxylated flavonols from Vellozia dasypus Seub ethyl acetate active myeloperoxidase extract: in vitro and in silico assays. J. Biomol. Struct. Dyn., 2022, 40(16), 7574-7583. doi: 10.1080/07391102.2021.1900916 PMID: 33739225Chang, H.; Li, C.; Wang, Q.; Lu, L.; Zhang, Q.; Zhang, Y.; Zhang, N.; Wang, Y.; Wang, W. QSKL protects against myocardial apoptosis on heart failure via PI3K/Akt-p53 signaling pathway. Sci. Rep., 2017, 7(1), 16986. doi: 10.1038/s41598-017-17163-x PMID: 29209026Zhang, Q.; Shao, M.; Zhang, X.; Wang, Q.; Guo, D.; Yang, X.; Li, C.; Wang, Y. The effect of chinese medicine on lipid and glucose metabolism in acute myocardial infarction through PPARγ pathway. Front. Pharmacol., 2018, 9, 1209. doi: 10.3389/fphar.2018.01209 PMID: 30405421Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461. PMID: 19499576Longde, W.; Ling, Y.; Yang, H.; Yi, Z.; Yongjun, W.; Xunming, J.; Xiaoyuan, N.; Qiumin, Q.; Li, H.; Yuming, X.; Mei, L.; Jiayi, S.; Jing, L.; Dong, Z. Fixed-dose combination treatment after stroke for secondary prevention in China: A national community-based study. Stroke, 2015, 46(5), 1295-1300. doi: 10.1161/STROKEAHA.114.007384 PMID: 25782466Foussas, S.G.; Tsiaousis, G.Z. Revascularization treatment in patients with coronary artery disease. Hippokratia, 2008, 12(1), 3-10. PMID: 18923757HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: Trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur. Heart J., 2008, 34(17), 1279-1291. PMID: 18923757Li, L.; Chen, X.; Su, C. Si-Miao-Yong-An decoction preserves cardiac function and regulates GLC/AMPK/NF-κB and GLC/PPARα/PGC-1α pathways in diabetic mice. Biomed. Pharmacother., 2020, 132, 110817.Patel, R.V.; Mistry, B.M.; Shinde, S.K.; Syed, R.; Singh, V.; Shin, H.S. Therapeutic potential of quercetin as a cardiovascular agent. Eur. J. Med. Chem., 2018, 155, 889-904. doi: 10.1016/j.ejmech.2018.06.053 PMID: 29966915Du, L.; Hao, M.; Li, C.; Wu, W.; Wang, W.; Ma, Z.; Yang, T.; Zhang, N.; Isaac, A.T.; Zhu, X.; Sun, Y.; Lu, Q.; Yin, X. Quercetin inhibited epithelial mesenchymal transition in diabetic rats, high-glucose-cultured lens, and SRA01/04 cells through transforming growth factor-β2/phosphoinositide 3-kinase/Akt pathway. Mol. Cell. Endocrinol., 2017, 452, 44-56. doi: 10.1016/j.mce.2017.05.011 PMID: 28501572Devi, K.P.; Malar, D.S.; Nabavi, S.F.; Sureda, A.; Xiao, J.; Nabavi, S.M.; Daglia, M. Kaempferol and inflammation: From chemistry to medicine. Pharmacol. Res., 2015, 99, 1-10. doi: 10.1016/j.phrs.2015.05.002 PMID: 25982933Feng, H.; Cao, J.; Zhang, G.; Wang, Y. Kaempferol attenuates cardiac hypertrophy via regulation of ASK1/MAPK signaling pathway and oxidative stress. Planta Med., 2017, 83(10), 837-845. doi: 10.1055/s-0043-103415 PMID: 28219095Yang, J.T.; Qian, L.B.; Zhang, F.J.; Wang, J.; Ai, H.; Tang, L.H.; Wang, H.P. Cardioprotective effects of luteolin on ischemia/reperfusion injury in diabetic rats are modulated by eNOS and the mitochondrial permeability transition pathway. J. Cardiovasc. Pharmacol., 2015, 65(4), 349-356. doi: 10.1097/FJC.0000000000000202 PMID: 25502309Koo, H.J.; Park, H.J.; Byeon, H.E.; Kwak, J.H.; Um, S.H.; Kwon, S.T.; Rhee, D.K.; Pyo, S. Chinese yam extracts containing β-sitosterol and ethyl linoleate protect against atherosclerosis in apolipoprotein E-deficient mice and inhibit muscular expression of VCAM-1 in vitro. J. Food Sci., 2014, 79(4), H719-H729. doi: 10.1111/1750-3841.12401 PMID: 24689699Gao, L.; Yao, R.; Liu, Y.; Wang, Z.; Huang, Z.; Du, B.; Zhang, D.; Wu, L.; Xiao, L.; Zhang, Y. Correction to: Isorhamnetin protects against cardiac hypertrophy through blocking PI3K–AKT pathway. Mol. Cell. Biochem., 2022, 477(1), 327-328. doi: 10.1007/s11010-021-04288-x PMID: 34741692Luo, Y.; Sun, G.; Dong, X.; Wang, M.; Qin, M.; Yu, Y.; Sun, X. Isorhamnetin attenuates atherosclerosis by inhibiting macrophage apoptosis via PI3K/AKT activation and HO-1 induction. PLoS One, 2015, 10(3), e0120259. doi: 10.1371/journal.pone.0120259 PMID: 25799286Hu, S.; Zhang, Y.; Zhang, M.; Guo, Y.; Yang, P.; Zhang, S.; Simsekyilmaz, S.; Xu, J.F.; Li, J.; Xiang, X.; Yu, Q.; Wang, C.Y. Aloperine protects mice against ischemia-reperfusion (IR)-induced renal injury by regulating PI3K/AKT/mTOR signaling and AP-1 activity. Mol. Med., 2015, 21(1), 912-923. doi: 10.2119/molmed.2015.00056 PMID: 26552059Liu, G.; Zhang, B.; Hu, Q.; Liu, X.; Chen, J. Syringic acid mitigates myocardial ischemia reperfusion injury by activating the PI3K/Akt/GSK-3β signaling pathway. Biochem. Biophys. Res. Commun., 2020, 531(2), 242-249. doi: 10.1016/j.bbrc.2020.07.047 PMID: 32798018Ding, Y.; Du, J.; Cui, F.; Chen, L.; Li, K. The protective effect of ligustrazine on rats with cerebral ischemia–reperfusion injury via activating PI3K/Akt pathway. Hum. Exp. Toxicol., 2019, 38(10), 1168-1177. doi: 10.1177/0960327119851260 PMID: 31250662Li, Z.; Zhao, F.; Cao, Y.; Zhang, J.; Shi, P.; Sun, X.; Zhang, F.; Tong, L. DHA attenuates hepatic ischemia reperfusion injury by inhibiting pyroptosis and activating PI3K/Akt pathway. Eur. J. Pharmacol., 2018, 835, 1-10. doi: 10.1016/j.ejphar.2018.07.054 PMID: 30075219Kaptoge, S.; Seshasai, S.R.K.; Gao, P.; Freitag, D.F.; Butterworth, A.S.; Borglykke, A.; Di Angelantonio, E.; Gudnason, V.; Rumley, A.; Lowe, G.D.O.; Jørgensen, T.; Danesh, J. Inflammatory cytokines and risk of coronary heart disease: New prospective study and updated meta-analysis. Eur. Heart J., 2014, 35(9), 578-589. doi: 10.1093/eurheartj/eht367 PMID: 24026779Gigante, B.; Strawbridge, R.J.; Velasquez, I.M.; Golabkesh, Z.; Silveira, A.; Goel, A.; Baldassarre, D.; Veglia, F.; Tremoli, E.; Clarke, R.; Watkins, H.; Hamsten, A.; Humphries, S.E.; de Faire, U. Analysis of the role of interleukin 6 receptor haplotypes in the regulation of circulating levels of inflammatory biomarkers and risk of coronary heart disease. PLoS One, 2015, 10(3), e0119980. doi: 10.1371/journal.pone.0119980 PMID: 25781951Perry, M.E. The regulation of the p53-mediated stress response by MDM2 and MDM4. Cold Spring Harb. Perspect. Biol., 2010, 2(1), a000968. doi: 10.1101/cshperspect.a000968 PMID: 20182601Wu, G.; Cai, J.; Han, Y.; Chen, J.; Huang, Z.P.; Chen, C.; Cai, Y.; Huang, H.; Yang, Y.; Liu, Y.; Xu, Z.; He, D.; Zhang, X.; Hu, X.; Pinello, L.; Zhong, D.; He, F.; Yuan, G.C.; Wang, D.Z.; Zeng, C. LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation, 2014, 130(17), 1452-1465. doi: 10.1161/CIRCULATIONAHA.114.011675 PMID: 25156994Zhang, Y.; Yang, X.; Bian, F.; Wu, P.; Xing, S.; Xu, G.; Li, W.; Chi, J.; Ouyang, C.; Zheng, T.; Wu, D.; Zhang, Y.; Li, Y.; Jin, S. TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: Crosstalk between NF-κB and PPAR-γ. J. Mol. Cell. Cardiol., 2014, 72, 85-94. doi: 10.1016/j.yjmcc.2014.02.012 PMID: 24594319Zhao, T.; Zhao, W.; Chen, Y.; Ahokas, R.A.; Sun, Y. Vascular endothelial growth factor (VEGF)-A: Role on cardiac angiogenesis following myocardial infarction. Microvasc. Res., 2010, 80(2), 188-194. doi: 10.1016/j.mvr.2010.03.014 PMID: 20362592Yue, T.L.; Wang, C.; Gu, J.L.; Ma, X.L.; Kumar, S.; Lee, J.C.; Feuerstein, G.Z.; Thomas, H.; Maleeff, B.; Ohlstein, E.H. Inhibition of extracellular signal-regulated kinase enhances Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ. Res., 2000, 86(6), 692-699. doi: 10.1161/01.RES.86.6.692 PMID: 10747006Wang, N.; Han, Y.; Tao, J.; Huang, M.; You, Y.; Zhang, H.; Liu, S.; Zhang, X.; Yan, C. Overexpression of CREG attenuates atherosclerotic endothelium apoptosis via VEGF/PI3K/AKT pathway. Atherosclerosis, 2011, 218(2), 543-551. doi: 10.1016/j.atherosclerosis.2011.08.002 PMID: 21872252Abeyrathna, P.; Su, Y. The critical role of Akt in cardiovascular function. Vascul. Pharmacol., 2015, 74, 38-48. doi: 10.1016/j.vph.2015.05.008 PMID: 26025205Cadenas, S. ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic. Biol. Med., 2018, 117, 76-89. doi: 10.1016/j.freeradbiomed.2018.01.024 PMID: 29373843Matusiak, A.; Chałubiński, M.; Broncel, M.; Rechciński, T.; Rudnicka, K.; Miszczyk, E.; Walencka, M.; Strapagiel, D.; Gajewski, A.; Chmiela, M. Putative consequences of exposure to Helicobacter pylori infection in patients with coronary heart disease in terms of humoral immune response and inflammation. Arch. Med. Sci., 2016, 1(1), 45-54. doi: 10.5114/aoms.2015.50772 PMID: 26925118Lee, S.I.; Lee, E.S.; El-Fiqi, A.; Lee, S.Y.; Kim, E-C.; Kim, H.W. Stimulation of odontogenesis and angiogenesis via bioactive nanocomposite calcium phosphate cements through integrin and VEGF signaling pathways. J. Biomed. Nanotechnol., 2016, 12(5), 1048-1062. doi: 10.1166/jbn.2016.2209 PMID: 27305825Chu, N.; Viennet, T.; Bae, H.; Salguero, A.; Boeszoermenyi, A.; Arthanari, H.; Cole, P.A. The structural determinants of PH domain-mediated regulation of Akt revealed by segmental labeling. eLife, 2020, 9, e59151. doi: 10.7554/eLife.59151 PMID: 32744507D’Andrea, L.D.; Iaccarino, G.; Fattorusso, R.; Sorriento, D.; Carannante, C.; Capasso, D.; Trimarco, B.; Pedone, C. Targeting angiogenesis: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide. Proc. Natl. Acad. Sci. USA, 2005, 102(40), 14215-14220. doi: 10.1073/pnas.0505047102 PMID: 16186493