Protective Effects of Liriodendrin on Myocardial Infarction-Induced Fibrosis in Rats via the PI3K/Akt Autophagy Pathway: A Network Pharmacology Study


Cite item

Full Text

Abstract

Background:Liriodendrin (LIR) has been reported to improve cardiac function in rats following myocardial infarction. However, its role and mechanism in reparative myocardial fibrosis remain unclear.

Methods:In this study, a rat model of myocardial fibrosis was established via left anterior descending artery ligation and randomly divided into three groups (n = 6 per group): sham-operated, myocardial infarction, and LIR intervention (100 mg/kg/day) groups. The pharmacological effects of LIR were assessed using echocardiography, hematoxylin, and eosin (H&E) staining, and Masson staining. Network pharmacology and bioinformatics were utilized to identify potential mechanisms of LIR, which were further validated via western blot analysis.

Results:Our findings demonstrated that LIR improved cardiac function, histology scores, and col lagen volume fraction. Moreover, LIR downregulated the expression of Beclin-1, LC3-II/LC3-I while upregulating the expression of p62, indicating LIR-inhibited autophagy in the heart after myocardial infarction. Further analysis revealed that the PI3K/Akt signaling pathway was significantly enriched and validated by western blot. This analysis suggested that the ratios of p- PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR were significantly increased.

Conclusion:LIR may attenuate myocardial infarction-induced fibrosis in rats by inhibiting excessive myocardial autophagy, with the potential mechanism involving the activation of the PI3K/Akt/mTOR pathway.

About the authors

Ping Zhang

Department of Cardiology, Tianjin Nankai Hospital

Email: info@benthamscience.net

Xuanming Liu

Graduate School, Tianjin University of Traditional Chinese Medicine

Email: info@benthamscience.net

Xin Yu

Graduate School, Tianjin University of Traditional Chinese Medicine

Email: info@benthamscience.net

Yuzhen Zhuo

Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital

Email: info@benthamscience.net

Dihua Li

Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital

Email: info@benthamscience.net

Lei Yang

Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital

Author for correspondence.
Email: info@benthamscience.net

Yanmin Lu

Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital

Author for correspondence.
Email: info@benthamscience.net

References

  1. Musher, D.M.; Abers, M.S.; Corrales-Medina, V.F. Acute infection and myocardial infarction. N. Engl. J. Med., 2019, 380(2), 171-176. doi: 10.1056/NEJMra1808137 PMID: 30625066
  2. Roger, V.L.; Go, A.S.; Lloyd-Jones, D.M.; Adams, R.J.; Berry, J.D.; Brown, T.M.; Carnethon, M.R.; Dai, S.; de Simone, G.; Ford, E.S.; Fox, C.S.; Fullerton, H.J.; Gillespie, C.; Greenlund, K.J.; Hailpern, S.M.; Heit, J.A.; Ho, P.M.; Howard, V.J.; Kissela, B.M.; Kittner, S.J.; Lackland, D.T.; Lichtman, J.H.; Lisabeth, L.D.; Makuc, D.M.; Marcus, G.M.; Marelli, A.; Matchar, D.B.; McDermott, M.M.; Meigs, J.B.; Moy, C.S.; Mozaffarian, D.; Mussolino, M.E.; Nichol, G.; Paynter, N.P.; Rosamond, W.D.; Sorlie, P.D.; Stafford, R.S.; Turan, T.N.; Turner, M.B.; Wong, N.D.; Wylie-Rosett, J. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation, 2011, 123(4), e18-e209. doi: 10.1161/CIR.0b013e3182009701 PMID: 21160056
  3. Abdallah, M.H.; Arnaout, S.; Karrowni, W.; Dakik, H.A. The management of acute myocardial infarction in developing countries. Int. J. Cardiol., 2006, 111(2), 189-194. doi: 10.1016/j.ijcard.2005.11.003 PMID: 16364475
  4. Barnes, M.; Heywood, A.E.; Mahimbo, A.; Rahman, B.; Newall, A.T.; Macintyre, C.R. Acute myocardial infarction and influenza: a meta-analysis of case–control studies. Heart, 2015, 101(21), 1738-1747. doi: 10.1136/heartjnl-2015-307691 PMID: 26310262
  5. Saleh, M.; Ambrose, J.A. Understanding myocardial infarction. F1000 Res., 2018, 7, 1378. doi: 10.12688/f1000research.15096.1 PMID: 30228871
  6. Lv, S.; Yuan, P.; Dong, J.; Lu, C.; Li, M.; Qu, F.; Zhu, Y.; Yuan, Z.; Zhang, J. QiShenYiQi pill improves the reparative myocardial fibrosis by regulating autophagy. J. Cell. Mol. Med., 2020, 24(19), 11283-11293. doi: 10.1111/jcmm.15695 PMID: 32881330
  7. Gatica, D.; Lahiri, V.; Klionsky, D.J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol., 2018, 20(3), 233-242. doi: 10.1038/s41556-018-0037-z PMID: 29476151
  8. Wang, X.; Dai, Y.; Ding, Z.; Khaidakov, M.; Mercanti, F.; Mehta, J.L. Regulation of autophagy and apoptosis in response to angiotensin II in HL-1 cardiomyocytes. Biochem. Biophys. Res. Commun., 2013, 440(4), 696-700. doi: 10.1016/j.bbrc.2013.09.131 PMID: 24099770
  9. Cătană, C.S.; Atanasov, A.G.; Berindan-Neagoe, I. Natural products with anti-aging potential: Affected targets and molecular mechanisms. Biotechnol. Adv., 2018, 36(6), 1649-1656. doi: 10.1016/j.biotechadv.2018.03.012 PMID: 29597027
  10. Wang, P.; Shao, B.Z.; Deng, Z.; Chen, S.; Yue, Z.; Miao, C.Y. Autophagy in ischemic stroke. Prog. Neurobiol., 2018, 163-164, 98-117. doi: 10.1016/j.pneurobio.2018.01.001 PMID: 29331396
  11. Matsui, Y.; Takagi, H.; Qu, X.; Abdellatif, M.; Sakoda, H.; Asano, T.; Levine, B.; Sadoshima, J. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res., 2007, 100(6), 914-922. doi: 10.1161/01.RES.0000261924.76669.36 PMID: 17332429
  12. Sciarretta, S.; Yee, D.; Nagarajan, N.; Bianchi, F.; Saito, T.; Valenti, V.; Tong, M.; Del Re, D.P.; Vecchione, C.; Schirone, L.; Forte, M.; Rubattu, S.; Shirakabe, A.; Boppana, V.S.; Volpe, M.; Frati, G.; Zhai, P.; Sadoshima, J. Trehalose-Induced Activation of Autophagy improves cardiac remodeling after myocardial infarction. J. Am. Coll. Cardiol., 2018, 71(18), 1999-2010. doi: 10.1016/j.jacc.2018.02.066 PMID: 29724354
  13. Sciarretta, S.; Yee, D.; Shenoy, V.; Nagarajan, N.; Sadoshima, J. The importance of autophagy in cardioprotection. High Blood Press. Cardiovasc. Prev., 2014, 21(1), 21-28. doi: 10.1007/s40292-013-0029-9 PMID: 24235024
  14. Li, Y.; Liu, M.; Song, X.; Zheng, X.; Yi, J.; Liu, D.; Wang, S.; Chu, C.; Yang, J. Exogenous hydrogen sulfide ameliorates diabetic myocardial fibrosis by inhibiting cell aging through SIRT6/AMPK autophagy. Front. Pharmacol., 2020, 11, 1150. doi: 10.3389/fphar.2020.01150 PMID: 32903815
  15. Ba, L.; Gao, J.; Chen, Y.; Qi, H.; Dong, C.; Pan, H.; Zhang, Q.; Shi, P.; Song, C.; Guan, X.; Cao, Y.; Sun, H. Allicin attenuates pathological cardiac hypertrophy by inhibiting autophagy via activation of PI3K/Akt/mTOR and MAPK/ERK/mTOR signaling pathways. Phytomedicine, 2019, 58, 152765. doi: 10.1016/j.phymed.2018.11.025 PMID: 31005720
  16. Heras-Sandoval, D.; Pérez-Rojas, J.M.; Hernández-Damián, J.; Pedraza-Chaverri, J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell. Signal., 2014, 26(12), 2694-2701. doi: 10.1016/j.cellsig.2014.08.019 PMID: 25173700
  17. Feng, C.; Li, B.G.; Gao, X.P.; Qi, H.Y.; Zhang, G.L. A new triterpene and an antiarrhythmic liriodendrin from Pittosporum brevicalyx. Arch. Pharm. Res., 2010, 33(12), 1927-1932. doi: 10.1007/s12272-010-1206-1 PMID: 21191756
  18. Jung, H.J.; Park, H.J.; Kim, R.G.; Shin, K.M.; Ha, J.; Choi, J.W.; Kim, H.J.; Lee, Y.S.; Lee, K.T. In vivo anti-inflammatory and antinociceptive effects of liriodendrin isolated from the stem bark of Acanthopanax senticosus. Planta Med., 2003, 69(7), 610-616. doi: 10.1055/s-2003-41127 PMID: 12898415
  19. Zhang, Z.; Yang, L.; Wang, B.; Zhang, L.; Zhang, Q.; Li, D.; Zhang, S.; Gao, H.; Wang, X. Protective role of liriodendrin in mice with dextran sulphate sodium-induced ulcerative colitis. Int. Immunopharmacol., 2017, 52, 203-210. doi: 10.1016/j.intimp.2017.09.012 PMID: 28941417
  20. Sohn, Y.A.; Hwang, S.A.; Lee, S.Y.; Hwang, I.Y.; Kim, S.W.; Kim, S.Y.; Moon, A.; Lee, Y.S.; Kim, Y.H.; Kang, K.J.; Jeong, C.S. Protective Effect of Liriodendrin Isolated from Kalopanax pictus against Gastric Injury. Biomol. Ther. (Seoul), 2015, 23(1), 53-59. doi: 10.4062/biomolther.2014.103 PMID: 25593644
  21. Kim, D.H.; Lee, K.T.; Bae, E.A.; Han, M.J.; Park, H.J. Metabolism of liriodendrin and syringin by human intestinal bacteria and their relation toin vitro cytotoxicity. Arch. Pharm. Res., 1999, 22(1), 30-34. doi: 10.1007/BF02976432 PMID: 10071956
  22. Li, G.; Yang, L.; Feng, L.; Yang, J.; Li, Y.; An, J.; Li, D.; Xu, Y.; Gao, Y.; Li, J.; Liu, J.; Yang, L.; Qi, Z. Syringaresinol Protects against Type 1 Diabetic Cardiomyopathy by Alleviating Inflammation Responses, Cardiac Fibrosis, and Oxidative Stress. Mol. Nutr. Food Res., 2020, 64(18), 2000231. doi: 10.1002/mnfr.202000231 PMID: 32729956
  23. Li, D.H.; Wang, Y.; Lv, Y.S.; Liu, J.H.; Yang, L.; Zhang, S.K.; Zhuo, Y.Z. Preparative Purification of Liriodendrin from Sargentodoxa cuneata by Macroporous Resin. BioMed Res. Int., 2015, 2015, 861256. PMID: 26236742
  24. Daina, A.; Michielin, O.; Zoete, V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res., 2019, 47(W1), W357-W364. doi: 10.1093/nar/gkz382 PMID: 31106366
  25. Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T.; Legeay, M.; Fang, T.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res., 2021, 49(D1), D605-D612. doi: 10.1093/nar/gkaa1074 PMID: 33237311
  26. Yu, T.; Wang, Z.; You, X.; Zhou, H.; He, W.; Li, B.; Xia, J.; Zhu, H.; Zhao, Y.; Yu, G.; Xiong, Y.; Yang, Y. Resveratrol promotes osteogenesis and alleviates osteoporosis by inhibiting p53. Aging (Albany NY), 2020, 12(11), 10359-10369. doi: 10.18632/aging.103262 PMID: 32459661
  27. Wu, T.; Hu, E.; Xu, S.; Chen, M.; Guo, P.; Dai, Z.; Feng, T.; Zhou, L.; Tang, W.; Zhan, L.; Fu, X.; Liu, S.; Bo, X.; Yu, G. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation, 2021, 2(3), 100141. doi: 10.1016/j.xinn.2021.100141 PMID: 34557778
  28. Chen, C.; Chen, H.; Zhang, Y.; Thomas, H.R.; Frank, M.H.; He, Y.; Xia, R. TBtools: An Integrative Toolkit Developed for Interactive Analyses of Big Biological Data. Mol. Plant, 2020, 13(8), 1194-1202. doi: 10.1016/j.molp.2020.06.009 PMID: 32585190
  29. Walter, W.; Sánchez-Cabo, F.; Ricote, M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics, 2015, 31(17), 2912-2914. doi: 10.1093/bioinformatics/btv300 PMID: 25964631
  30. Park, S.; Nguyen, N.B.; Pezhouman, A.; Ardehali, R. Cardiac fibrosis: potential therapeutic targets. Transl. Res., 2019, 209, 121-137. doi: 10.1016/j.trsl.2019.03.001 PMID: 30930180
  31. Aujla, P.K.; Kassiri, Z. Diverse origins and activation of fibroblasts in cardiac fibrosis. Cell. Signal., 2021, 78, 109869. doi: 10.1016/j.cellsig.2020.109869 PMID: 33278559
  32. Mavrogeni, S.; Markousis-Mavrogenis, G.; Koutsogeorgopoulou, L.; Kolovou, G. Cardiovascular magnetic resonance imaging: clinical implications in the evaluation of connective tissue diseases. J. Inflamm. Res., 2017, 10, 55-61. doi: 10.2147/JIR.S115508 PMID: 28546762
  33. Samsamshariat, S.A.; Samsamshariat, Z.A.; Movahed, M.R. A novel method for safe and accurate left anterior descending coronary artery ligation for research in rats. Cardiovasc. Revasc. Med., 2005, 6(3), 121-123. doi: 10.1016/j.carrev.2005.07.001 PMID: 16275608
  34. Schirone, L.; Forte, M.; Palmerio, S.; Yee, D.; Nocella, C.; Angelini, F.; Pagano, F.; Schiavon, S.; Bordin, A.; Carrizzo, A.; Vecchione, C.; Valenti, V.; Chimenti, I.; De Falco, E.; Sciarretta, S.; Frati, G. A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling. Oxid. Med. Cell. Longev., 2017, 2017, 1-16. doi: 10.1155/2017/3920195 PMID: 28751931
  35. Jung, C.H.; Jun, C.B.; Ro, S.H.; Kim, Y.M.; Otto, N.M.; Cao, J.; Kundu, M.; Kim, D.H. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell, 2009, 20(7), 1992-2003. doi: 10.1091/mbc.e08-12-1249 PMID: 19225151
  36. Lv, S.; Yuan, P.; Lu, C.; Dong, J.; Li, M.; Qu, F.; Zhu, Y.; Zhang, J. QiShenYiQi pill activates autophagy to attenuate reactive myocardial fibrosis via the PI3K/AKT/mTOR pathway. Aging, 2021, 13(4), 5525-5538. doi: 10.18632/aging.202482 PMID: 33582656

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers