J Appl Biomed 21:137-149, 2023 | DOI: 10.32725/jab.2023.014

Guanxinning tablets improve myocardial hypertrophy by inhibiting the activation of MEK-ERK1/2 signaling pathway

Yan Zhang1, 2, Yu Huang2, Quan-xin Ma2, Song-tao Xu3, Liye Shen3, Yan-yun Xu3, Hai-ye Tu3, Min-li Chen2, Yi-li Rong2, *
1 Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314000, China
2 Zhejiang Chinese Medical University, Academy of Chinese Medicine & Institute of Comparative Medicine, Hangzhou 310053, China
3 Zhejiang Chinese Medical University, College of Pharmacy, Hangzhou 310053, China

Myocardial hypertrophy may lead to heart failure and sudden death. As traditional Chinese medicine, Guanxinning tablets (GXN) have significant pharmacological effects in the prevention and treatment of cardiovascular diseases. However, the anti-cardiac hypertrophy efficacy of GXN and its mechanism of action are still unclear. Therefore, we established a heart failure rat model and isolated primary cardiomyocytes of neonatal rat to observe the protective effect of GXN on heart failure rat model and the intervention effect on myocardial cell hypertrophy, and to explore the possible mechanism of GXN preventing and treating myocardial hypertrophy. The results of in vivo experiments showed that GXN could significantly reduce the degree of cardiac hypertrophy, reduce the size of cardiomyocytes, inhibit the degree of myocardial remodeling and fibrosis, and improve cardiac function in rats with early heart failure. The results of in vitro experiments showed that GXN was safe for primary cardiomyocytes and could improve cardiomyocyte hypertrophy and reduce the apoptosis of cardiomyocytes in pathological state, which may be related to the inhibition of the over-activation of MEK-ERK1/2 signaling pathway. In conclusion, GXN may inhibit cardiac hypertrophy and improve early heart failure by inhibiting the over-activation of MEK-ERK1/2 signaling pathway.

Keywords: Early heart failure; Guanxinning tablet; MEK-ERK1, 2 signaling pathway; Myocardial hypertrophy
Grants and funding:

The project received support from the Jiaxing Science and Technology Planning Project (No. 2019AY32023), Jiaxing Key disciplines of Traditional Chinese Medicine support class – Chinese Pharmacy, (NO. Jiawei [2023] 65), Jiaxing Hospital of Traditional Chinese Medicine “Teaching Excellence” Special Program (NO. 2021JXZY019) and Research Project of Zhejiang Chinese Medical University (No. 2021JKZKTS031B).

Conflicts of interest:

The authors have no conflict of interest to declare.

Received: October 25, 2022; Revised: September 1, 2023; Accepted: September 15, 2023; Prepublished online: September 18, 2023; Published: September 22, 2023  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Zhang Y, Huang Y, Ma Q, Xu S, Shen L, Xu Y, et al.. Guanxinning tablets improve myocardial hypertrophy by inhibiting the activation of MEK-ERK1/2 signaling pathway. J Appl Biomed. 2023;21(3):137-149. doi: 10.32725/jab.2023.014. PubMed PMID: 37747313.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Bavendiek U, Berliner D, Dávila LA, Schwab J, Maier L, Philipp SA, et al. (2019). Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study. Eur J Heart Fail 21(5): 676-684. DOI: 10.1002/ejhf.1452. Go to original source... Go to PubMed...
    2. Bueno OF, Molkentin JD (2002). Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res 91(9): 776-781. DOI: 10.1161/01.res.0000038488.38975.1a. Go to original source... Go to PubMed...
    3. Chen ML, Lv JM, Pan YM, Ying HZ, Guan MW, Zhang JB, et al. (2005a). Effect of Guanxinning Tablet in Acute Myocardial Ischemia in Beagle Dogs. J Zhejiang Chin Med Univ 29(4): 54-56. DOI: 10.16466/j.issn1005-5509.2005.04.034. Go to original source...
    4. Chen ML, Shou QY, Pan YM, Zhang JB, Sang R, Guan MW, et al. (2005b). Inhibitive and protective effects of guanxinning tablets on platelet aggregation and vascular endothelium in qi stagnation and blood stasis rat. Chin J Clin Pharm Ther 10(5): 586-589. DOI: 10.3969/j.issn.1009-2501.2005.05.024. Go to original source...
    5. Chen ML, Wang H, Lin L, Shou QY, Zhou WM, Wang DJ, et al. (2006). Effect of Guanxinning Tablet on Hemorrheology in Aged Rats. Lab Anim Comp Med 26(4): 231-234. DOI: 10.3969/j.issn.1674-5817.2006.04.007. Go to original source...
    6. Chen X, Lou Z, Zhang H, et al. (2011). Identification of multiple components in Guanxinning injection using hydrophilic interaction liquid chromatography/time-of-flight mass spectrometry and reversed-phase liquid chromatography/time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 25(11): 1661-1674. DOI: 10.1002/rcm.5003. Go to original source... Go to PubMed...
    7. Gu J, Hu W, Song ZP, Chen YG, Zhang DD, Wang CQ, et al. (2016). Rapamycin Inhibits Cardiac Hypertrophy by Promoting Autophagy via the MEK/ERK/Beclin-1 Pathway. Front Physiol 7: 104. DOI: 10.3389/fphys.2016.00104. Go to original source... Go to PubMed...
    8. Hu C, Dai F, Wang J, Jiang L, Wang D, Gao J, et al. (2022). Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice. Oxid Med Cell Longev 2022: 5067544. DOI: 10.1155/2022/5067544. Go to original source... Go to PubMed...
    9. Hu F, Rong YL, Zhu KY, Lu H, Chen C, Chen ML, Pan YM (2017). Study on the protective effect of Guanxinning Tablet on myocardial ischemia reperfusion injury in rats. Chin J Comp Med 27(5): 76-82. DOI: 10.3969.j.issn.1671-7856.2017.05.017.
    10. Huang Y, Ni N, Hong Y, Lin X, Feng Y, Shen L (2020). Progress in Traditional Chinese Medicine for the Treatment of Migraine. Am J Chin Med 48(8): 1731-1748. DOI: 10.1142/S0192415X2050086X. Go to original source... Go to PubMed...
    11. Iyer NR, Le TT, Kui MSL, Tang HC, Chin CT, Phua SK, et al. (2022). Markers of Focal and Diffuse Nonischemic Myocardial Fibrosis Are Associated With Adverse Cardiac Remodeling and Prognosis in Patients With Hypertension: The REMODEL Study. Hypertension 79(8): 1804-1813. DOI: 10.1161/HYPERTENSIONAHA.122.19225. Go to original source... Go to PubMed...
    12. Kan M, Wang J, Ming S, Sui X, Zhang Z, Yang Q, et al. (2022). Investigating the Mechanism of Shengmaiyin (Codonopsis pilosula) in the Treatment of Heart Failure Based on Network Pharmacology. Comb Chem High Throughput Screen 25(13): 2191-2202. DOI: 10.2174/1386207325666220221093415. Go to original source... Go to PubMed...
    13. Ko SY, Lin IH, Shieh TM, Ko HA, Chen HI, Chi TC, et al. (2013). Cell hypertrophy and MEK/ERK phosphorylation are regulated by glyceraldehyde-derived AGEs in cardiomyocyte H9c2 cells. Cell Biochem Biophys 66(3): 537-544. DOI: 10.1007/s12013-012-9501-8. Go to original source... Go to PubMed...
    14. Li W, Yang J, Lyu Q, Wu G, Lin S, Yang Q, Hu J (2020). Taurine attenuates isoproterenol-induced H9c2 cardiomyocytes hypertrophy by improving antioxidative ability and inhibiting calpain-1-mediated apoptosis. Mol Cell Biochem 469(1-2): 119-132. DOI: 10.1007/s11010-020-03733-7. Go to original source... Go to PubMed...
    15. Litwin SE, Katz SE, Weinberg EO, Lorell BH, Aurigemma GP, Douglas PS (1995). Serial echocardiographic-Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy. Chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure. Circulation 91(10): 2642-2654. DOI: 10.1161/01.cir.91.10.2642. Go to original source... Go to PubMed...
    16. Liu M, Ye J, Gao S, Fang W, Li H, Geng B, et al. (2014). Salvianolic acid B protects cardiomyocytes from angiotensin II-induced hypertrophy via inhibition of PARP-1. Biochem Biophys Res Commun 444(3): 346-353. DOI: 10.1016/j.bbrc.2014.01.045. Go to original source... Go to PubMed...
    17. Livak KJ, Schmittgen TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4): 402-408. DOI: 10.1006/meth.2001.1262. Go to original source... Go to PubMed...
    18. Lorenz K, Schmitt JP, Vidal M, Lohse MJ (2009). Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. Int J Biochem Cell Biol 41(12): 2351-2355. DOI: 10.1016/j.biocel.2009.08.002. Go to original source... Go to PubMed...
    19. Luo M, Lin HC, Wen ZQ, Chen PP, Shi WL, Li YY, et al. (2022). Sodium Ferulate Inhibits Rat Cardiomyocyte Hypertrophy Induced by Angiotensin II Through Enhancement of Endothelial Nitric Oxide Synthase/Nitric Oxide/Cyclic Guanosine Monophosphate Signaling Pathway. J Cardiovasc Pharmacol 80(2): 251-260. DOI: 10.1097/FJC.0000000000001277. Go to original source... Go to PubMed...
    20. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. (2022). 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 24(1): 4-131. DOI: 10.1002/ejhf.2333. Go to original source... Go to PubMed...
    21. Messerli H, Bangalore S, Bavishi C, Rimoldi SF (2018). Angiotensin-Converting Enzyme Inhibitors in Hypertension: To Use or Not to Use? J Am Coll Cardiol 71(13): 1474-1482. DOI: 10.1016/j.jacc.2018.01.058. Go to original source... Go to PubMed...
    22. Ming S, Kan M, Liu L, Zhang Z, Liu X, Liu Y, et al. (2022). Protective Effect of Shengmaiyin in Myocardial Hypertrophy-Induced Rats: A Genomic Analysis by 16S rDNA. Evid Based Complement Alternat Med 2022: 3188292. DOI: 10.1155/2022/3188292. Go to original source... Go to PubMed...
    23. Nakamura M, Sadoshima J (2018). Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15(7): 387-407. DOI: 10.1038/s41569-018-0007-y. Go to original source... Go to PubMed...
    24. Olson BJ (2016). Assays for Determination of Protein Concentration. Curr Protoc Prarmacol 73:A.3A.1-A.3A.32. DOI: 10.1002/cpph.3. Go to original source... Go to PubMed...
    25. Pan YM, Ying HZ, Chen ML, Xu JQ, Zhou WM, Wang H, et al. (2007). Effects of Guanxinninga Tablet on Myocardial Oxygen Consumption in Dogs. Lab Anim Comp Med 27(3): 190-194. DOI: 10.3969/j.issn.1674-5817.2007.03.011. Go to original source...
    26. Panico K, Abrahao MV, Trentin-Sonoda M, Muzi-Filho H, Vieyra A, Carneiro-Ramos MS (2019). Cardiac Inflammation after Ischemia-Reperfusion of the Kidney: Role of the Sympathetic Nervous System and the Renin-Angiotensin System. Cell Physiol Biochem 53(4): 587-605. DOI: 10.33594/000000159. Go to original source... Go to PubMed...
    27. Persoon-Rothert M, van der Wees KG, van der Laarse A (2002). Mechanical overload-induced apoptosis: a study in cultured neonatal ventricular myocytes and fibroblasts. Mol Cell Biochem 241(1-2): 115-124. DOI: 10.1023/a:1020860209333. Go to original source... Go to PubMed...
    28. Ponikowska B, Iwanek G, Zdanowicz A, Urban S, Zymliñski R, Ponikowski P, Biegus J (2022). Biomarkers of Myocardial Injury and Remodeling in Heart Failure. J Pers Med 12(5). DOI: 10.3390/jpm12050799. Go to original source... Go to PubMed...
    29. Ruan M, Li Y, Li X, Luo J, Kong L (2012). Qualitative and quantitative analysis of the major constituents in Chinese medicinal preparation Guan-Xin-Ning injection by HPLC-DAD-ESI-MS(n). J Pharm Biomed Anal 59: 184-189. DOI: 10.1016/j.jpba.2011.10.007. Go to original source... Go to PubMed...
    30. Savage P, Cox B, Linden K, Coburn J, Shahmohammadi M, Menown I (2022). Advances in Clinical Cardiology 2021: A Summary of Key Clinical Trials. Adv Ther 39(6): 2398-2437. DOI: 10.1007/s12325-022-02136-y. Go to original source... Go to PubMed...
    31. Shang H, Zhang J, Yao C, Liu B, Gao X, Ren M, et al. (2013). Qi-shen-yi-qi dripping pills for the secondary prevention of myocardial infarction: a randomised clinical trial. Evid Based Complement Alternat Med 2013: 738391. DOI: 10.1155/2013/738391. Go to original source... Go to PubMed...
    32. Shen DF, Wu QQ, Ni J, Deng W, Wei C, Jia ZH, et al. (2016). Shensongyangxin protects against pressure overload‑induced cardiac hypertrophy. Mol Med Rep 13(1): 980-988. DOI: 10.3892/mmr.2015.4598. Go to original source... Go to PubMed...
    33. Shi L, Wang S, Zangari M, Xu H, Cao TM, Xu C, et al. (2010). Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. Oncotarget 1(1): 22-33. DOI: 10.18632/oncotarget.105. Go to original source... Go to PubMed...
    34. Sun MY, Miao Y, Jin M, Dong YR, Liu SR, Wang ML, Gao R (2019). Effect and Safety of Guanxinning Tablet ( ) for Stable Angina Pectoris Patients with Xin (Heart)-Blood Stagnation Syndrome: A Randomized, Multicenter, Placebo-Controlled Trial. Chin J Integr Med 25(9): 684-690. DOI: 10.1007/s11655-019-3069-8. Go to original source... Go to PubMed...
    35. Tang Y, Wang M, Le X, Meng J, Huang L, Yu P, et al. (2011). Antioxidant and cardioprotective effects of Danshensu (3-(3, 4-dihydroxyphenyl)-2-hydroxy-propanoic acid from Salvia miltiorrhiza) on isoproterenol-induced myocardial hypertrophy in rats. Phytomedicine 18(12): 1024-1030. DOI: 10.1016/j.phymed.2011.05.007. Go to original source... Go to PubMed...
    36. Walker JM (1994). The bicinchoninic acid (BCA) assay for protein quantitation. Methods Mol Biol 32: 5-8. DOI: 10.1385/0-89603-268-X:5. Go to original source... Go to PubMed...
    37. Wang L, Li Z, Wang C, Yang Y, Sun L, Yao W, et al. (2009). E-cadherin decreased human breast cancer cells sensitivity to staurosporine by up-regulating Bcl-2 expression. Arch Biochem Biophys 481(1): 116-122. DOI: 10.1016/j.abb.2008.10.021. Go to original source... Go to PubMed...
    38. Wang L, Wang S, Jia T, Sun X, Xing Z, Liu H, et al. (2022). Dexmedetomidine prevents cardiomyocytes from hypoxia/reoxygenation injury via modulating tetmethylcytosine dioxygenase 1-mediated DNA demethylation of Sirtuin1. Bioengineered 13(4): 9369-9386. DOI: 10.1080/21655979.2022.2054762. Go to original source... Go to PubMed...
    39. Wang ML, Yang QQ, Ying XH, Li YY, Wu YS, Shou QY, et al. (2020). Network Pharmacology-Based Approach Uncovers the Mechanism of GuanXinNing Tablet for Treating Thrombus by MAPKs Signal Pathway. Front Pharmacol 11. DOI: ARTN 65210.3389/fphar.2020.00652. Go to original source... Go to PubMed...
    40. Wang Y, Wang Q, Li C, Lu L, Zhang Q, Zhu R, et al. (2017). A Review of Chinese Herbal Medicine for the Treatment of Chronic Heart Failure. Curr Pharm Des 23(34): 5115-5124. DOI: 10.2174/1381612823666170925163427. Go to original source... Go to PubMed...
    41. Watanabe H, Iwanaga Y, Miyaji Y, Yamamoto H, Miyazaki S (2016). Renal denervation mitigates cardiac remodeling and renal damage in Dahl rats: a comparison with beta-receptor blockade. Hypertens Res 39(4): 217-226. DOI: 10.1038/hr.2015.133. Go to original source... Go to PubMed...
    42. Xing H, Zhang S, Weinheimer C, Kovacs A, Muslin AJ (2000). 14-3-3 proteins block apoptosis and differentially regulate MAPK cascades. EMBO J 19(3): 349-358. DOI: 10.1093/emboj/19.3.349. Go to original source... Go to PubMed...
    43. Xu L, Chen L, Gu G, Wang Y, Xu Y, Zhong Y (2022). Natural products from traditional Chinese medicine for the prevention and treatment of heart failure: progress and perspectives. Rev Cardiovasc Med 23(2): 60. DOI: 10.31083/j.rcm2302060. Go to original source... Go to PubMed...
    44. Xu X, Ruan L, Tian X, Pan F, Yang C, Liu G (2020). Calcium inhibitor inhibits high glucose‑induced hypertrophy of H9C2 cells. Mol Med Rep 22(3): 1783-1792. DOI: 10.3892/mmr.2020.11275. Go to original source... Go to PubMed...
    45. You Y, Luo L, You Y, Lin Y, Hu H, Chen Y, et al. (2020). Shengmai Yin formula modulates the gut microbiota of spleen-deficiency rats. Chin Med 15: 114. DOI: 10.1186/s13020-020-00394-y. Go to original source... Go to PubMed...
    46. Zang Y, Wan J, Zhang Z, Huang S, Liu X, Zhang W (2020). An updated role of astragaloside IV in heart failure. Biomed Pharmacother 126: 110012. DOI: 10.1016/j.biopha.2020.110012. Go to original source... Go to PubMed...
    47. Zhang (2017). Research progress of Salvia miltiorrhizae Chuanxiong and its formulation Guanxining Preparation in the treatment of cardiovascular and cerebrovascular diseases. Chin Tradit Pat Med 39(05): 1018-1024. DOI:10.3969/j.issn.1001-1528.2017.05.029. Go to original source...
    48. Zhang B, He P, Lu Y, Bian X, Yang X, Fu X, et al. (2015). HSF1 Relieves Amyloid-beta-Induced Cardiomyocytes Apoptosis. Cell Biochem Biophys 72(2): 579-587. DOI: 10.1007/s12013-014-0505-4. Go to original source... Go to PubMed...
    49. Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, et al. (2000). TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat Med 6(5): 556-563. DOI: 10.1038/75037. Go to original source... Go to PubMed...
    50. Zhang M, Chen Y, Chen H, Shen Y, Pang L, Wu W, Yu Z (2022). Tanshinone IIA alleviates cardiac hypertrophy through m6A modification of galectin-3. Bioengineered 13(2): 4260-4270. DOI: 10.1080/21655979.2022.2031388. Go to original source... Go to PubMed...
    51. Zhang X, Zhang MC, Wang CT (2018). Loss of LRRC25 accelerates pathological cardiac hypertrophy through promoting fibrosis and inflammation regulated by TGF-beta 1. Biochem Bioph Res Co 506(1): 137-144. DOI: 10.1016/j.bbrc.2018.09.065. Go to original source... Go to PubMed...
    52. Zhang Y, Cai S, Ding X, Lu C, Wu R, Wu H, et al. (2021). MicroRNA-30a-5p silencing polarizes macrophages toward M2 phenotype to alleviate cardiac injury following viral myocarditis by targeting SOCS1. Am J Physiol Heart Circ Physiol 320(4): H1348-H1360. DOI: 10.1152/ajpheart.00431.2020. Go to original source... Go to PubMed...
    53. Zhao Y, Li Y, Tong L, Liang X, Zhang H, Li L, et al. (2018). Analysis of microRNA Expression Profiles Induced by Yiqifumai Injection in Rats with Chronic Heart Failure. Front Physiol 9: 48. DOI: 10.3389/fphys.2018.00048. Go to original source... Go to PubMed...

    This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0), which permits non-comercial use, distribution, and reproduction in any medium, provided the original publication is properly cited. No use, distribution or reproduction is permitted which does not comply with these terms.


    Return to the content