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Huoxin Pill (活心丸) Attenuates Cardiac Fibrosis by Suppressing TGF-β1/Smad2/3 Pathway in Isoproterenol-Induced Heart Failure Rats

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Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To evaluate the effects of Huoxin Pill (活心丸, HXP) on cardiac fibrosis and heart failure (HF) in isoproterenol (ISO)-induced HF rats.

Methods

Thirty Wistar rats were randomly divided into 5 groups including control, HF, isosorbide mononitrate (ISMN), HXP low (HXP-L), and HXP high (HXP-H) groups (n=6 for each group) according to the complete randomization method. Rats were pretreated with ISMN (5 mg/kg daily), low concentration of HXP (10 mg/kg daily) or high concentration of HXP (30 mg/kg daily) or equal volume of saline by intragastric administration for 1 week, followed by intraperitoneal injection of ISO (10 mg/kg, 14 days), and continually intragastric administrated with above medicines or saline for additional 6 weeks. The effects of HXP treatment on the cardiac function, heart weight index (HWI), pathological changes, and collagen content were further assessed. Moreover, the role of HXP on activation of transforming growth factor- β 1 (TGF-β 1)/Smads pathway was further explored using immunohistochemistry (IHC) and Western-blot assay.

Results

HXP treatment significantly alleviated the decrease of ejection fraction (EF) and fractional shortening (FS), while decreased the elevation of left ventricular end-systolic volume (LVESV) in ISO-induced HF rats (P<0.05). Moreover, HXP treatment obviously attenuated the increase of HWI and serum level of creatine kinase MB (CK-MB, P<0.05), as well as pathological changes in ISO-induced HF rats. Further determination indicated that HXP treatment alleviated the elevation of collagen I and collagen III protein expression in cardiac tissues of ISO-induced HF rats. Furthermore, HXP treatment significantly down-regulated the increase of TGF-β 1 and p-Smad2/3 protein expression in cardiac tissues of HF rats (P<0.05), while did not affect the expression of total Smad2/3.

Conclusions

HXP attenuated heart failure and cardiac fibrosis in ISO-induced HF rats by suppression of TGF-β 1/Smad2/3 pathway.

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References

  1. Pagliaro BR, Cannata F, Stefanini GG, Bolognese L. Myocardial ischemia and coronary disease in heart failure. Heart Fail Rev 2020;25:53–65.

    Article  Google Scholar 

  2. Shah RV, Rong J, Larson MG, Yeri A, Ziegler O, Tanriverdi K, et al. Associations of circulating extracellular RNAs with myocardial remodeling and heart failure. JAMA Cardiol 2018;3:871–876.

    Article  Google Scholar 

  3. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015;131:e329–e322.

    Google Scholar 

  4. Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397–1402.

    Article  Google Scholar 

  5. Januzzi JL, Butler J, Fombu E, Maisel A, McCague K, Piña IL, et al. Rationale and methods of the prospective study of biomarkers, symptom improvement, and ventricular remodeling during sacubitril/valsartan therapy for heart failure (PROVE-HF). Am Heart J 2018;199:130–136.

    Article  Google Scholar 

  6. Bacmeister L, Schwarzl M, Warnke S, Stoffers B, Blankenberg S, Westermann D, et al. Inflammation and fibrosis in murine models of heart failure. Basic Res Cardiol 2019;114:19.

    Article  CAS  Google Scholar 

  7. Dobaczewski M, Bujak M, Li N, Gonzalez-Quesada C, Mendoza LH, Wang XF, et al. Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circ Res 2010 6;107:418–428.

    Article  CAS  Google Scholar 

  8. Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 2007;74:184–195.

    Article  CAS  Google Scholar 

  9. Tandon A, Tovey JC, Sharma A, Gupta R, Mohan RR. Role of transforming growth factor beta in corneal function, biology and pathology. Curr Mol Med 2010;10:565–578.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Hao J, Ju H, Zhao S, Junaid A, Scammell-La Fleur T, Dixon IM. Elevation of expression of Smads 2, 3, and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. J Mol Cell Cardiol 1999;31:667–678.

    Article  CAS  Google Scholar 

  11. Ikeuchi M, Tsutsui H, Shiomi T, Matsusaka H, Matsushima S, Wen J, et al. Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc Res 2004;64:526–535.

    Article  CAS  Google Scholar 

  12. Zeng Z, Wang Q, Yang X, Ren Y, Jiao S, Zhu Q, et al. Qishen granule attenuates cardiac fibrosis by regulating TGF-β/Smad3 and GSK-3β pathway. Phytomedicine 2019;62:152949.

    Article  Google Scholar 

  13. Han A, Lu Y, Zheng Q, Zhang J, Zhao Y, Zhao M, et al. Qiliqiangxin attenuates cardiac remodeling via inhibition of TGF- β 1/Smad3 and NF- κ B signaling pathways in a rat model of myocardial infarction. Cell Physiol Biochem 2018;45:1797–1806.

    Article  CAS  Google Scholar 

  14. Wang QW, Yu XF, Xu HL, Zhao XZ, Sui DY. Ginsenoside Re improves isoproterenol-induced myocardial fibrosis and heart failure in rats. Evid Based Complement Alternat Med 2019;2019:3714508.

    PubMed  PubMed Central  Google Scholar 

  15. Gong P, Li Y, Yao C, Guo H, Hwang H, Liu X, et al. Traditional Chinese medicine on the treatment of coronary heart disease in recent 20 years. J Altern Complement Med 2017;23:659–666.

    Article  Google Scholar 

  16. Akila P, Asaikumar L, Vennila L. Chlorogenic acid ameliorates isoproterenol-induced myocardial injury in rats by stabilizing mitochondrial and lysosomal enzymes. Biomed Pharmacother 2017;85:582–591.

    Article  CAS  Google Scholar 

  17. Rani S, Sreenivasaiah PK, Kim JO, Lee MY, Kang WS, Kim YS, et al. Tauroursodeoxycholic acid (TUDCA) attenuates pressure overload-induced cardiac remodeling by reducing endoplasmic reticulum stress. PLoS One 2017;12:e0176071.

    Article  CAS  Google Scholar 

  18. Li P, Song Q, Liu T, Wu Z, Chu X, Zhang X, et al. Inhibitory effect of cinobufagin on L-type Ca2+ currents, contractility, and Ca2+ homeostasis of isolated adult rat ventricular myocytes. Sci World J 2014;2014:496705.

    Google Scholar 

  19. Wu X, Li M, Chen SQ, Li S, Guo F. Pin1 facilitates isoproterenol-induced cardiac fibrosis and collagen deposition by promoting oxidative stress and activating the MEK1/2-ERK1/2 signal transduction pathway in rats. Int J Mol Med 2018;41:1573–1583.

    PubMed  CAS  Google Scholar 

  20. Marks AR. Calcium cycling proteins and heart failure: mechanisms and therapeutics. J Clin Invest 2013;123:46–52.

    Article  CAS  Google Scholar 

  21. Lu LH, Li C, Wang QY, Zhang Q, Zhang Y, Meng H, et al. Cardioprotective effects of Qishen Granule on sarcoplasmic reticulum Ca2+ handling in heart failure rats. Chin J Integr Med 2017;23:510–517.

    Article  CAS  Google Scholar 

  22. Wang YC, Ma DF, Jiang P, Zhang YM, Zhou GF, Yang JL, et al. Guizhi Decoction inhibits cholinergic transdifferentiation by regulating imbalance of NGF and LIF in salt-sensitive hypertensive heart failure rats. Chin J Integr Med 2020;26:188–196.

    Article  CAS  Google Scholar 

  23. Yang H, Zhang FF, Peng XH, Zhao DH, Peng J. Efficacy of medication directed by home-monitoring cardiac resynchronization therapy in chronic heart failure patients. Chin Med Sci J 2014;29:61–62.

    Article  CAS  Google Scholar 

  24. Li L, Hao J, Jiang X, Li P, Sen H. Cardioprotective effects of ulinastatin against isoproterenol-induced chronic heart failure through the PI3K-Akt, p38 MAPK and NF-κ B pathways. Mol Med Rep 2018;17:1354–1360.

    PubMed  CAS  Google Scholar 

  25. Wang JJ, Rau C, Avetisyan R, Ren S, Romay MC, Stolin G, et al. Genetic dissection of cardiac remodeling in an isoproterenol-induced heart failure mouse model. PLoS Genet 2016;12:e1006038.

    Article  CAS  Google Scholar 

  26. Mohamed SS, Ahmed LA, Attia WA, Khattab MM. Nicorandil enhances the efficacy of mesenchymal stem cell therapy in isoproterenol-induced heart failure in rats. Biochem Pharmacol 2015;98:403–411.

    Article  CAS  Google Scholar 

  27. Siman FD, Silveira EA, Fernandes AA, Stefanon I, Vassallo DV, Padilha AS. Ouabain induces nitric oxide release by a PI3K/Akt-dependent pathway in isolated aortic rings from rats with heart failure. J Cardiovasc Pharmacol 2015;65:28–38.

    Article  CAS  Google Scholar 

  28. Sanderson JE. New treatments for myocardial fibrosis. Cardiovasc Drugs Ther 2002;16:181–182.

    Article  CAS  Google Scholar 

  29. Lok DJ, Lok SI, Bruggink-André de la Porte PW, Badings E, Lipsic E, van Wijngaarden J, et al. Galectin-3 is an independent marker for ventricular remodeling and mortality in patients with chronic heart failure. Clin Res Cardiol 2013;102:103–110.

    Article  CAS  Google Scholar 

  30. Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-β signaling in fibrosis. Growth Factors 2011;29:196–202.

    Article  CAS  Google Scholar 

  31. Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor-beta 1. Mol Genet Metab 2000;71:418–435.

    Article  CAS  Google Scholar 

  32. ten Dijke P, Arthur HM. Extracellular control of TGF beta signalling in vascular development and disease. Nat Rev Mol Cell Biol 2007;8:857–869.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

    Mei-zhong Peng, A-ling Shen, Xue-ling Zhou, Yan Lu, Zhi-qing Shen, Bin Huang, Jun Peng & Jian-feng Chu

  2. Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

    Mei-zhong Peng, A-ling Shen, Xue-ling Zhou, Yan Lu, Zhi-qing Shen, Bin Huang, Jun Peng & Jian-feng Chu

  3. Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

    Mei-zhong Peng, A-ling Shen, Xue-ling Zhou, Yan Lu, Zhi-qing Shen, Bin Huang, Jun Peng & Jian-feng Chu

  4. The Third People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

    Mei-ling Yang

  5. Department of Research and Development, Youcare Pharmaceutical Group Co., Ltd., Beijing, 100176, China

    Qi Li

Authors
  1. Mei-zhong Peng
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  2. Mei-ling Yang
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  3. A-ling Shen
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  4. Xue-ling Zhou
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  5. Yan Lu
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  6. Qi Li
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  7. Zhi-qing Shen
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  8. Bin Huang
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  9. Jun Peng
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  10. Jian-feng Chu
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Contributions

Chu JF and Peng MZ conceived and designed the experiments. Peng MZ, Yang ML, Shen AL and Zhou XL created the models. Lu Y and Shen ZQ performed the experiments. Huang B analyzed the data. Li Q contributed reagents/materials/analysis tools. Peng MZ drafted the manuscript. Chu JF and Peng J revised the manuscript.

Corresponding author

Correspondence to Jian-feng Chu.

Additional information

Conflict of Interest

HXP in this study was presented by Youcare Biopharmaceutics Co., Ltd., and LI Qi is the marketing director of the company. There is no potential conflict of interest among other authors.

Supported by the National Natural Science Foundation of China (No. 81774135 and No. 81302884), Science and Technology Major Project of Fujian Province (No. 2019YZ014004), Natural Science Foundations of Fujian Province (No. 2018J01884), and Fujian Provincial Health and Family Planning Commission (No. 2018-CX-42)

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Peng, Mz., Yang, Ml., Shen, Al. et al. Huoxin Pill (活心丸) Attenuates Cardiac Fibrosis by Suppressing TGF-β1/Smad2/3 Pathway in Isoproterenol-Induced Heart Failure Rats. Chin. J. Integr. Med. 27, 424–431 (2021). https://doi.org/10.1007/s11655-020-2862-8

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  • DOI: https://doi.org/10.1007/s11655-020-2862-8

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