Journal of Traditional Chinese Medicine >
Optimized new Shengmai powder (优化新生脉散方) inhibits myocardial fibrosis in heart failure by regulating the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway
Received date: 2023-01-16
Accepted date: 2023-05-25
Online published: 2024-04-02
Supported by
Innovation Team Development Program of the Ministry of Education: Research on the Prevention and Treatment of Cardiovascular Diseases with Traditional Chinese Medicine(IRT-16R54)
OBJECTIVE: Exploring the effect of Optimized New Shengmai powder (优化新生脉散方, ONSMP) on myocardial fibrosis in heart failure (HF) based on rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathway.
METHODS: Randomized 70 Sprague-Dawley rats into sham (n = 10) and operation (n = 60) groups, then established the HF rat by ligating the left anterior descending branch of the coronary artery. We randomly divided the operation group rats into the model, ONSMP [including low (L), medium (M), and high (H) dose], and enalapril groups. After the 4-week drug intervention, echocardiography examines the cardiac function and calculates the ratios of the whole/left heart to the rat's body weight. Finally, we observed the degree of myocardial fibrosis by pathological sections, determined myocardium collagen (COL) I and COL Ⅲ content by enzyme-linked immunosorbent assay, detected the mRNA levels of COL I, COL Ⅲ, α-smooth muscle actin (α-SMA), and c-Fos proto-oncogene (c-Fos) by universal real-time, and detected the protein expression of p-RAS, p-RAF, p-MEK1/2, p-ERK1/2, p-ETS-like-1 transcription factor (p-ELK1), p-c-Fos, α-SMA, COL I, and COL Ⅲ by Western blot.
RESULTS: ONSMP can effectively improve HF rat's cardiac function, decrease cardiac organ coefficient, COL volume fraction, and COL I/Ⅲ content, down-regulate the mRNA of COL I/Ⅲ, α-SMA and c-Fos, and the protein of p-RAS, p-RAF, p-MEK1/ 2, p-ERK1/2, p-ELK1, c-Fos, COL Ⅰ/Ⅲ, and α-SMA.
CONCLUSIONS: ONSMP can effectively reduce myocardial fibrosis in HF rats, and the mechanism may be related to the inhibition of the RAS/RAF/MEK/ERK signaling pathway.
Zeyu ZHANG , Zhuangzhuang JIA , Yuwei SONG , Xuan ZHANG , Ci WANG , Shuai WANG , Peipei ZHANG , Qiuan REN , Xianliang WANG , Jingyuan MAO . Optimized new Shengmai powder (优化新生脉散方) inhibits myocardial fibrosis in heart failure by regulating the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway[J]. Journal of Traditional Chinese Medicine, 2024 , 44(3) : 448 -457 . DOI: 10.19852/j.cnki.jtcm.20240402.004
| 1. | McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599-726. |
| 2. | Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2022 update: a report from the american heart association. Circulation 2022; 145: e153-639. |
| 3. | González A, Schelbert EB, Díez J, Butler J. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol 2018; 71:1696-706. |
| 4. | Marunouchi T, Nakashima M, Ebitani S, et al. Hsp90 inhibitor attenuates the development of pathophysiological cardiac fibrosis in mouse hypertrophy via suppression of the calcineurin-NFAT and c-Raf-Erk pathways. J Cardiovasc Pharmacol 2021; 77: 822-9. |
| 5. | Chen M, Li H, Wang G, Shen X, Zhao S, Su W. Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-γ). Metabolism 2016; 65: 441-53. |
| 6. | García-Martín A, Navarrete C, Garrido-Rodríguez M, et al. EHP-101 alleviates angiotensin Ⅱ-induced fibrosis and inflammation in mice. Biomed Pharmacother 2021; 142: 112007. |
| 7. | Mao JY, Zhu MJ. Expert consensus on Traditional Chinese Medicine diagnosis and treatment of chronic heart failure. Zhong Yi Za Zi 2014; 55: 1258-60. |
| 8. | Wang XL, Yuan Y, Mao JY, et al. A single-case crossover randomized controlled study of optimized new Shengmai powder combined with Western medicine in the treatment of chronic heart failure. Zhong Yi Za Zi 2015; 56: 1849-53. |
| 9. | Pang L, Mao JY, Wan CJ, Wang S. Study on the protective effect of New Shengmai powder optimized prescription on adriamycin-induced myocardial injury in mice. Jilin Zhong Yi Yao 2012; 32: 712-5. |
| 10. | Zhang ZY, Wang XL, Wang S, Jia ZZ, Yan HF, Mao JY. Based on network pharmacology and molecular docking technology to explore the mechanism of optimized new Shengmai powder in anti-myocardial fibrosis in chronic heart failure. Henan Zhong Yi 2022; 42: 1032-9. |
| 11. | Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res 2021; 117: 1450-88. |
| 12. | Piek A, Silljé HHW, de Boer RA. The vicious cycle of arrhythmia and myocardial fibrosis. Eur J Heart Fail 2019; 21: 492-4. |
| 13. | Park S, Nguyen NB, Pezhouman A, Ardehali R. Cardiac fibrosis: potential therapeutic targets. Transl Res 2019; 209: 121-37. |
| 14. | Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation 2022; 145: e895-1032. |
| 15. | Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res 2016; 365: 563-81. |
| 16. | Zhou R, Han B, Xia C, Zhuang X. Membrane-associated periodic skeleton is a signaling platform for RTK transactivation in neurons. Science 2019; 365: 929-34. |
| 17. | Jain R, Watson U, Vasudevan L, Saini DK. ERK activation pathways downstream of GPCRs. Int Rev Cell Mol Biol 2018; 338: 79-109. |
| 18. | Chen Z, Oh D, Dubey AK, et al. EGFR family and Src family kinase interactions: mechanics matters. Curr Opin Cell Biol 2018; 51: 97-102. |
| 19. | Hu M, He W, Gao P, et al. Virus-induced accumulation of intracellular bile acids activates the TGR5-β-arrestin-SRC axis to enable innate antiviral immunity. Cell Res 2019; 29: 193-205. |
| 20. | Smith JS, Pack TF, Inoue A, et al. Noncanonical scaffolding of G(αi) and β-arrestin by G protein-coupled receptors. Science 2021;371: eaay1833. |
| 21. | Arkun Y, Yasem Mi. Dynamics and control of the ERK signaling pathway: sensitivity, bistability, and oscillations. PloS One 2018; 13: e195513. |
| 22. | Xie K, Colgan LA, Dao MT, et al. NF1 is a direct G protein effector essential for opioid signaling to Ras in the striatum. Curr Biol 2016; 26: 2992-3003. |
| 23. | Rodríguez-álvarez FJ, Jiménez-Mora E, Caballero M, Gallego B, Chiloeches A, Toro MJ. Somatostatin activates Ras and ERK1/2 via a G protein βγ-subunit-initiated pathway in thyroid cells. Mol Cell Biochem 2016; 411: 253-60. |
| 24. | Cui N, Li L, Feng Q, Ma HM, Lei D, Zheng PS. Hexokinase 2 promotes cell growth and tumor formation through the Raf/MEK/ERK signaling pathway in cervical cancer. Front Oncol 2020; 10: 581208. |
| 25. | Cheng Y, Zhu Y, Xu J, et al. PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-ERK1/2 pathway. Mol Cancer 2018; 17: 13. |
| 26. | Zhou Y, Shiok TC, Richards AM, Wang P. MicroRNA-101a suppresses fibrotic programming in isolated cardiac fibroblasts and in vivo fibrosis following trans-aortic constriction. J Mol Cell Cardiol 2018; 121: 266-76. |
| 27. | Ulrich M, Wissenbach U, Thiel G. The super-cooling compound icilin stimulates c-Fos and Egr-1 expression and activity involving TRPM8 channel activation, Ca2+ ion influx and activation of the ternary complex factor ELK1. Biochem Pharmacol 2020; 177: 113936. |
| 28. | Tallquist MD. Cardiac fibroblast diversity. Annu Rev Physiol 2020; 82: 63-78. |
| 29. | Tallquist MD, Molkentin JD. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol 2017; 14: 484-91. |
| 30. | Deng T, Karin M. c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK. Nature 1994. 371: 171-5. |
| 31. | Chen RH, Abate C, Blenis J. Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase. Proc Natl Acad Sci USA 1993; 9: 10952-6. |
| 32. | Peng B, Zhu H, Ma L, Wang YL, Klausen C, Leung PC. AP-1 transcription factors c-Fos and c-JUN mediate GnRH-induced cadherin-11 expression and trophoblast cell invasion. Endocrinology 2015; 156: 2269-77. |
| 33. | Hattori Y, Hattori S, Akimoto K, et al. Globular adiponectin activates nuclear factor-kappa B and activating protein-1 and enhances angiotensin Ⅱ-induced proliferation in cardiac fibroblasts. Diabetes 2007; 56: 804-8. |
| 34. | Kovary K, Bravo R. The Jun and Fos protein families are both required for cell cycle progression in fibroblasts. Mol Cell Biol 1991; 11: 4466-72. |
| 35. | Ou W, Ni N, Zuo R, et al. Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence. Oncogene 2019; 38: 6615-29. |
| 36. | Rodriguez-Pascual F, Slatter DA. Collagen cross-linking: insights on the evolution of metazoan extracellular matrix. Sci Rep 2016; 6: 37374. |
| 37. | Lee W, Mitchell P, Tjian R. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell 1987; 49: 741-52. |
| 38. | Jia J, Ye T, Cui P, Hua Q, Zeng H, Zhao D. AP-1 transcription factor mediates VEGF-induced endothelial cell migration and proliferation. Microvasc Res 2016; 105: 103-8. |
| 39. | Ryseck RP, Bravo R. c-JUN, JUN B, and JUN D differ in their binding affinities to AP-1 and CRE consensus sequences: effect of FOS proteins. Oncogene 1991; 6: 533-42. |
| 40. | Kovary K, Bravo R. Existence of different Fos/Jun complexes during the G0-to-G1 transition and during exponential growth in mouse fibroblasts: differential role of Fos proteins. Mol Cell Biol 1992; 12: 5015-23. |
| 41. | Humeres C, Shinde AV, Hanna A, et al. Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure. J Clin Invest 2022; 13: e146926. |
/
| 〈 |
|
〉 |