Research overview of myocardial fibrosis and extracellular signal-regulated kinase pathway in chronic heart failure_West China Medical Journal

Authors：

ZHANG Zeyu , WANG Xianliang , HOU Yazhu , WANG Shuai , JIA Zhuangzhuang ,  MAO Jingyuan

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, P. R. China;

Corresponding author：

MAO Jingyuan, Email: jymao@126.com

Keywords：

Chronic heart failure; myocardial fibrosis; extracellular signal-regulated kinase

DOI：

10.7507/1002-0179.202110047

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

The fundamental reason why the organic lesions of chronic heart failure are difficult to reverse is ventricular remodeling. Myocardial fibrosis (MF) is an important pathological basis of ventricular remodeling. Its development process involves complex biological mechanisms and neuroendocrine system. Extracellular signal-regulated kinase (ERK) pathway is a classic pathway for the treatment of tumors. It is found that the inhibition of the ERK pathway can also slow down the progressive aggravation of MF. Therefore, exploring the mechanism of ERK pathway in MF may provide a new idea for the prevention and treatment of chronic heart failure. In this paper, the mechanism of ERK pathway in the occurrence and development of MF and its inhibition drugs were described, in order to provide evidence for the prevention and treatment of MF in chronic heart failure based on this pathway.

Citation： ZHANG Zeyu, WANG Xianliang, HOU Yazhu, WANG Shuai, JIA Zhuangzhuang, MAO Jingyuan. Research overview of myocardial fibrosis and extracellular signal-regulated kinase pathway in chronic heart failure. West China Medical Journal, 2022, 37(4): 610-614. doi: 10.7507/1002-0179.202110047 Copy

1.	中华医学会心血管病学分会心力衰竭学组, 中国医师协会心力衰竭专业委员会, 中华心血管病杂志编辑委员会. 中国心力衰竭诊断和治疗指南 2018. 中华心力衰竭和心肌病杂志(中英文), 2018, 2(4): 196-225.
2.	Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart. Kardiol Pol, 2016, 74(10): 1037-1147.
3.	Abi-Samra F, Gutterman D. Cardiac contractility modulation: a novel approach for the treatment of heart failure. Heart Fail Rev, 2016, 21(6): 645-660.
4.	Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res, 2016, 365(3): 563-581.
5.	González A, Schelbert EB, Díez J, et al. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol, 2018, 71(15): 1696-1706.
6.	Piek A, Silljé HHW, de Boer RA. The vicious cycle of arrhythmia and myocardial fibrosis. Eur J Heart Fail, 2019, 21(4): 492-494.
7.	Park S, Nguyen NB, Pezhouman A, et al. Cardiac fibrosis: potential therapeutic targets. Transl Res, 2019, 209: 121-137.
8.	Li X, Yang Y, Chen S, et al. Epigenetics-based therapeutics for myocardial fibrosis. Life Sci, 2021, 271: 119186.
9.	Rai V, Sharma P, Agrawal S, et al. Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol Cell Biochem, 2017, 424(1-2): 123-145.
10.	López B, Ravassa S, Moreno MU, et al. Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches. Nat Rev Cardiol, 2021, 18(7): 479-498.
11.	Çelik Ö, Şahin AA, Sarıkaya S, et al. Correlation between serum matrix metalloproteinase and myocardial fibrosis in heart failure patients with reduced ejection fraction: a retrospective analysis. Anatol J Cardiol, 2020, 24(5): 303-308.
12.	Takawale A, Zhang P, Patel VB, et al. Tissue inhibitor of matrix metalloproteinase-1 promotes myocardial fibrosis by mediating CD63-integrin β1 interaction. Hypertension, 2017, 69(6): 1092-1103.
13.	Sato C, Yamamoto Y, Funayama E, et al. Conditioned medium obtained from amnion-derived mesenchymal stem cell culture prevents activation of keloid fibroblasts. Plast Reconstr Surg, 2018, 141(2): 390-398.
14.	Gibb AA, Lazaropoulos MP, Elrod JW. Myofibroblasts and fibrosis: mitochondrial and metabolic control of cellular differentiation. Circ Res, 2020, 127(3): 427-447.
15.	Ma ZG, Yuan YP, Wu HM, et al. Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci, 2018, 14(12): 1645-1657.
16.	Wang H, Liu S, Liu S, et al. Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-Ⅱ stimulation. PLoS One, 2017, 12(6): e178530.
17.	Tian X, Sun C, Wang X, et al. ANO1 regulates cardiac fibrosis via ATI-mediated MAPK pathway. Cell Calcium, 2020, 92: 102306.
18.	Zhou R, Han B, Xia C, et al. Membrane-associated periodic skeleton is a signaling platform for RTK transactivation in neurons. Science, 2019, 365(6456): 929-934.
19.	Jain R, Watson U, Vasudevan L, et al. ERK activation pathways downstream of GPCRs. Int Rev Cell Mol Biol, 2018, 338: 79-109.
20.	Kang LL, Zhang DM, Jiao RQ, et al. Pterostilbene attenuates fructose-induced myocardial fibrosis by inhibiting ROS-driven Pitx2c/miR-15b Pathway. Oxid Med Cell Longev, 2019, 2019: 1243215.
21.	Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest, 2017, 127(10): 3770-3783.
22.	Henri O, Pouehe C, Houssari M, et al. Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction. Circulation, 2016, 133(15): 1484-1497.
23.	Chen S, Zhang Y, Lighthouse JK, et al. A novel role of cyclic nucleotide phosphodiesterase 10A in pathological cardiac remodeling and dysfunction. Circulation, 2020, 141(3): 217-233.
24.	Yang T, Zhang H, Liang Q, et al. Small-conductance Ca²⁺-activated potassium channels negatively regulate aldosterone secretion in human adrenocortical cells. Hypertension, 2016, 68(3): 785-795.
25.	Bersi MR, Bellini C, Wu J, et al. Excessive adventitial remodeling leads to early aortic maladaptation in angiotensin-induced hypertension. Hypertension, 2016, 67(5): 890-896.
26.	Froogh G, Pinto JT, Le Y, et al. Chymase-dependent production of angiotensinⅡ: an old enzyme in old hearts. Am J Physiol Heart Circ Physiol, 2017, 312(2): H223-H231.
27.	Forrester SJ, Booz GW, Sigmund CD, et al. Angiotensin Ⅱ signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev, 2018, 98(3): 1627-1738.
28.	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.
29.	Hu M, He WR, 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(3): 193-205.
30.	Smith JS, Pack TF, Inoue A, et al. Noncanonical scaffolding of G_αi and β-arrestin by G protein-coupled receptors. Science, 2021, 371(6534): eaay1833.
31.	Kazi JU, Rönnstrand L. The role of SRC family kinases in FLT3 signaling. Int J Biochem Cell Biol, 2019, 107: 32-37.
32.	Arkun Y, Yasemi M. Dynamics and control of the ERK signaling pathway: sensitivity, bistability, and oscillations. PloS One, 2018, 13(4): e0195513.
33.	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(22): 2992-3003.
34.	Rodríguez-Álvarez FJ, Jiménez-Mora E, Caballero M, et al. Somatostatin activates Ras and ERK1/2 via a G protein βγ-subunit-initiated pathway in thyroid cells. Mol Cell Biochem, 2016, 411(1/2): 253-260.
35.	Cui N, Li L, Feng Q, et al. Hexokinase 2 promotes cell growth and tumor formation through the Raf/MEK/ERK signaling pathway in cervical cancer. Front Oncol, 2020, 10: 581208.
36.	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(1): 13.
37.	Zhou Y, Shiok TC, Richards AM, et al. MicroRNA-101a suppresses fibrotic programming in isolated cardiac fibroblasts and in vivo fibrosis following trans-aortic constriction. J Mol Cell Cardiol, 2018, 121: 266-276.
38.	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 Elk-1. Biochem Pharmacol, 2020, 177: 113936.
39.	Tallquist MD. Cardiac Fibroblast Diversity. Annu Rev Physiol, 2020, 82: 63-78.
40.	Tallquist MD, Molkentin JD. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol, 2017, 14(8): 484-491.
41.	Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: is the undruggable drugged. Nat Rev Drug Discov, 2020, 19(8): 533-552.
42.	Li L, Fang H, Yu Y, et al. Liquiritigenin attenuates isoprenaline-induced myocardial fibrosis in mice through the TGF-β1/Smad2 and AKT/ERK signaling pathways. Mol Med Rep, 2021, 24(4): 686.
43.	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(6): 822-829.
44.	Chen M, Li H, Wang G, et al. Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-γ). Metabolism, 2016, 65(4): 441-453.
45.	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.
46.	Feng W, Zhao Y, Song X, et al. Zi Shen Huo Luo Formula prevents aldosterone-induced cardiomyocyte hypertrophy and cardiac fibroblast proliferation by regulating the striatin-mediated MR/EGFR/ERK signaling pathway. Evid Based Complement Alternat Med, 2020, 2020: 9028047.
47.	Meng H, Du Z, Lu W, et al. Baoyuan decoction (BYD) attenuates cardiac hypertrophy through ANKRD1-ERK/GATA4 pathway in heart failure after acute myocardial infarction. Phytomedicine, 2021, 89: 153617.
48.	Han CK, Kuo WW, Shen CY, et al. Dilong prevents the high-KCl cardioplegic solution administration-induced apoptosis in H9c2 cardiomyoblast cells mediated by MEK. Am J Chin Med, 2014, 42(6): 1507-1519.

1. 中华医学会心血管病学分会心力衰竭学组, 中国医师协会心力衰竭专业委员会, 中华心血管病杂志编辑委员会. 中国心力衰竭诊断和治疗指南 2018. 中华心力衰竭和心肌病杂志(中英文), 2018, 2(4): 196-225.
2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart. Kardiol Pol, 2016, 74(10): 1037-1147.
3. Abi-Samra F, Gutterman D. Cardiac contractility modulation: a novel approach for the treatment of heart failure. Heart Fail Rev, 2016, 21(6): 645-660.
4. Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res, 2016, 365(3): 563-581.
5. González A, Schelbert EB, Díez J, et al. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol, 2018, 71(15): 1696-1706.
6. Piek A, Silljé HHW, de Boer RA. The vicious cycle of arrhythmia and myocardial fibrosis. Eur J Heart Fail, 2019, 21(4): 492-494.
7. Park S, Nguyen NB, Pezhouman A, et al. Cardiac fibrosis: potential therapeutic targets. Transl Res, 2019, 209: 121-137.
8. Li X, Yang Y, Chen S, et al. Epigenetics-based therapeutics for myocardial fibrosis. Life Sci, 2021, 271: 119186.
9. Rai V, Sharma P, Agrawal S, et al. Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol Cell Biochem, 2017, 424(1-2): 123-145.
10. López B, Ravassa S, Moreno MU, et al. Diffuse myocardial fibrosis: mechanisms, diagnosis and therapeutic approaches. Nat Rev Cardiol, 2021, 18(7): 479-498.
11. Çelik Ö, Şahin AA, Sarıkaya S, et al. Correlation between serum matrix metalloproteinase and myocardial fibrosis in heart failure patients with reduced ejection fraction: a retrospective analysis. Anatol J Cardiol, 2020, 24(5): 303-308.
12. Takawale A, Zhang P, Patel VB, et al. Tissue inhibitor of matrix metalloproteinase-1 promotes myocardial fibrosis by mediating CD63-integrin β1 interaction. Hypertension, 2017, 69(6): 1092-1103.
13. Sato C, Yamamoto Y, Funayama E, et al. Conditioned medium obtained from amnion-derived mesenchymal stem cell culture prevents activation of keloid fibroblasts. Plast Reconstr Surg, 2018, 141(2): 390-398.
14. Gibb AA, Lazaropoulos MP, Elrod JW. Myofibroblasts and fibrosis: mitochondrial and metabolic control of cellular differentiation. Circ Res, 2020, 127(3): 427-447.
15. Ma ZG, Yuan YP, Wu HM, et al. Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci, 2018, 14(12): 1645-1657.
16. Wang H, Liu S, Liu S, et al. Enhanced expression and phosphorylation of Sirt7 activates smad2 and ERK signaling and promotes the cardiac fibrosis differentiation upon angiotensin-Ⅱ stimulation. PLoS One, 2017, 12(6): e178530.
17. Tian X, Sun C, Wang X, et al. ANO1 regulates cardiac fibrosis via ATI-mediated MAPK pathway. Cell Calcium, 2020, 92: 102306.
18. Zhou R, Han B, Xia C, et al. Membrane-associated periodic skeleton is a signaling platform for RTK transactivation in neurons. Science, 2019, 365(6456): 929-934.
19. Jain R, Watson U, Vasudevan L, et al. ERK activation pathways downstream of GPCRs. Int Rev Cell Mol Biol, 2018, 338: 79-109.
20. Kang LL, Zhang DM, Jiao RQ, et al. Pterostilbene attenuates fructose-induced myocardial fibrosis by inhibiting ROS-driven Pitx2c/miR-15b Pathway. Oxid Med Cell Longev, 2019, 2019: 1243215.
21. Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest, 2017, 127(10): 3770-3783.
22. Henri O, Pouehe C, Houssari M, et al. Selective stimulation of cardiac lymphangiogenesis reduces myocardial edema and fibrosis leading to improved cardiac function following myocardial infarction. Circulation, 2016, 133(15): 1484-1497.
23. Chen S, Zhang Y, Lighthouse JK, et al. A novel role of cyclic nucleotide phosphodiesterase 10A in pathological cardiac remodeling and dysfunction. Circulation, 2020, 141(3): 217-233.
24. Yang T, Zhang H, Liang Q, et al. Small-conductance Ca²⁺-activated potassium channels negatively regulate aldosterone secretion in human adrenocortical cells. Hypertension, 2016, 68(3): 785-795.
25. Bersi MR, Bellini C, Wu J, et al. Excessive adventitial remodeling leads to early aortic maladaptation in angiotensin-induced hypertension. Hypertension, 2016, 67(5): 890-896.
26. Froogh G, Pinto JT, Le Y, et al. Chymase-dependent production of angiotensinⅡ: an old enzyme in old hearts. Am J Physiol Heart Circ Physiol, 2017, 312(2): H223-H231.
27. Forrester SJ, Booz GW, Sigmund CD, et al. Angiotensin Ⅱ signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev, 2018, 98(3): 1627-1738.
28. 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.
29. Hu M, He WR, 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(3): 193-205.
30. Smith JS, Pack TF, Inoue A, et al. Noncanonical scaffolding of G_αi and β-arrestin by G protein-coupled receptors. Science, 2021, 371(6534): eaay1833.
31. Kazi JU, Rönnstrand L. The role of SRC family kinases in FLT3 signaling. Int J Biochem Cell Biol, 2019, 107: 32-37.
32. Arkun Y, Yasemi M. Dynamics and control of the ERK signaling pathway: sensitivity, bistability, and oscillations. PloS One, 2018, 13(4): e0195513.
33. 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(22): 2992-3003.
34. Rodríguez-Álvarez FJ, Jiménez-Mora E, Caballero M, et al. Somatostatin activates Ras and ERK1/2 via a G protein βγ-subunit-initiated pathway in thyroid cells. Mol Cell Biochem, 2016, 411(1/2): 253-260.
35. Cui N, Li L, Feng Q, et al. Hexokinase 2 promotes cell growth and tumor formation through the Raf/MEK/ERK signaling pathway in cervical cancer. Front Oncol, 2020, 10: 581208.
36. 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(1): 13.
37. Zhou Y, Shiok TC, Richards AM, et al. MicroRNA-101a suppresses fibrotic programming in isolated cardiac fibroblasts and in vivo fibrosis following trans-aortic constriction. J Mol Cell Cardiol, 2018, 121: 266-276.
38. 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 Elk-1. Biochem Pharmacol, 2020, 177: 113936.
39. Tallquist MD. Cardiac Fibroblast Diversity. Annu Rev Physiol, 2020, 82: 63-78.
40. Tallquist MD, Molkentin JD. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol, 2017, 14(8): 484-491.
41. Moore AR, Rosenberg SC, McCormick F, et al. RAS-targeted therapies: is the undruggable drugged. Nat Rev Drug Discov, 2020, 19(8): 533-552.
42. Li L, Fang H, Yu Y, et al. Liquiritigenin attenuates isoprenaline-induced myocardial fibrosis in mice through the TGF-β1/Smad2 and AKT/ERK signaling pathways. Mol Med Rep, 2021, 24(4): 686.
43. 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(6): 822-829.
44. Chen M, Li H, Wang G, et al. Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-γ). Metabolism, 2016, 65(4): 441-453.
45. 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.
46. Feng W, Zhao Y, Song X, et al. Zi Shen Huo Luo Formula prevents aldosterone-induced cardiomyocyte hypertrophy and cardiac fibroblast proliferation by regulating the striatin-mediated MR/EGFR/ERK signaling pathway. Evid Based Complement Alternat Med, 2020, 2020: 9028047.
47. Meng H, Du Z, Lu W, et al. Baoyuan decoction (BYD) attenuates cardiac hypertrophy through ANKRD1-ERK/GATA4 pathway in heart failure after acute myocardial infarction. Phytomedicine, 2021, 89: 153617.
48. Han CK, Kuo WW, Shen CY, et al. Dilong prevents the high-KCl cardioplegic solution administration-induced apoptosis in H9c2 cardiomyoblast cells mediated by MEK. Am J Chin Med, 2014, 42(6): 1507-1519.

West China Medical Journal

Research overview of myocardial fibrosis and extracellular signal-regulated kinase pathway in chronic heart failure

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content