Regulation of TGF-β1/JNK signaling pathway in patients with different types of mitral valve diseases complicated by atrial fibrillation_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

CHANG Chao ¹ , FU Bo ¹ , ZHU Xiaolong ¹ , ZHANG Chongjie ² , ZHAO Xia ³ , TANG Hong ⁴ ,  XIAO Xijun ⁵ ,  BAI Yunpeng ¹

1. Department of Cardiovascular Surgery, Tianjin Chest Hospital, Tianjin University, Tianjin, 300222, P. R. China;
2. Department of Immunology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, P. R. China;
3. Laboratory of Gynecological Oncology Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, P. R. China;
4. Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China;
5. Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China;

Corresponding author：

XIAO Xijun, Email: xijunxiao1952@163.com; BAI Yunpeng, Email: oliverwhite@126.com

Keywords：

Atrial fibrillation; mitral valve disease; TGF-β1/JNK signaling pathway; apoptosis; atrial structural remodeling

DOI：

10.7507/1007-4848.202507006

Video：

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Objective To investigate the regulatory mechanism of transforming growth factor-β1 (TGF-β1) in different types of mitral valvular disease (MVD) with atrial fibrillation (AF). Methods From August 2011 to August 2012, 16 patients with moderate to severe MVD accompanied by AF who required mitral valve replacement at the Department of Cardiovascular Surgery, West China Hospital, Sichuan University, were included. Based on echocardiographic results, patients were divided into two groups: a mitral regurgitation (MR) with AF (MR-AF) group and a mitral stenosis (MS) with AF (MS-AF) group. Left atrial tissue samples were collected during surgery. Techniques such as enzyme-linked immunosorbent assay, real-time fluorescence quantitative polymerase chain reaction, immunohistochemistry, and Western blotting were used to detect key molecules in the TGF-β1/JNK pathway. Results There were 8 patients in the MR-AF group, including 5 males and 3 females, with an average age of (41.38±11.19) years; and 8 patients in the MS-AF group, including 6 males and 2 females, with an average age of (43.12±5.30) years. The left atrial volume load was higher in MR-AF patients, while the left atrial pressure load was higher in MS-AF patients. In MS-AF patients, the relative expression levels of MAPK9, JUN, CASP3, BAX, and BCL2 mRNA in left atrial tissues were significantly upregulated. The serum TGF-β1 protein level and the relative expression levels of p-JNK, p-c-Jun, and Caspase-3 proteins in the left atrial tissues of the MR-AF group were higher. Myocardial cell damage was more severe in the MS-AF group, and the expression level of Bcl-2 was higher. Conclusion Different mitral valve lesions have distinct hemodynamic characteristics. The myocardium of the left atrium in MR-AF patients is more prone to apoptosis, possibly through the activation of the TGF-β1/JNK signaling pathway.

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2.	Chen LW, Li QZ, Chen JY, et al. A new procedure for elimination of atrial fibrillation associated with mitral valve disease: a proof-of-concept study. Int J Surg, 2023, 109(10): 2914-2925.
3.	Chang C, Zhang CJ, Zhao X, et al. Differential regulation of mitogen-activated protein kinase signaling pathways in human with different types of mitral valvular disease. J Surg Res, 2013, 181(1): 49-59.
4.	Qian YJ, Meng J, Tang H, et al. Different structural remodeling in atrial fibrillation with different types of mitral valvular diseases. Europace, 2010, 12(3): 371-377.
5.	Beyer C, Tokarska L, Stühlinger M, et al. Structural cardiac remodeling in atrial fibrillation. JACC Cardiovasc Imaging, 2021, 14(11): 2199-2208.
6.	Molnár AÁ, Sánta A, Pásztor DT, et al. Atrial cardiomyopathy in valvular heart disease: from molecular biology to clinical perspectives. Cells, 2023, 12(13): 1796.
7.	Deng ZQ, Fan T, Xiao C, et al. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther, 2024, 9(1): 61.
8.	Zhu EY, Liu Y, Zhong M, et al. Targeting NK-1R attenuates renal fibrosis via modulating inflammatory responses and cell fate in chronic kidney disease. Front Immunol, 2023, 14: 1142240.
9.	Xie SY, Song SC, Liu SR, et al. (Pro)renin receptor mediates tubular epithelial cell pyroptosis in diabetic kidney disease via DPP4-JNK pathway. J Transl Med, 2024, 22(1): 26.
10.	Gehi BR, Gadhave K, Uversky VN, et al. Intrinsic disorder in proteins associated with oxidative stress-induced JNK signaling. Cell Mol Life Sci, 2022, 79(4): 202.
11.	Nadel G, Maik-Rachline G, Seger R. JNK cascade-induced apoptosis-a unique role in GqPCR signaling. Int J Mol Sci, 2023, 24(17): 13527.
12.	Nikolic I, Leiva M, Sabio G. The role of stress kinases in metabolic disease. Nat Rev Endocrinol, 2020, 16(12): 697-716.
13.	Babapoor-Farrokhran S, Tarighati Rasekhi R, Gill D, et al. How transforming growth factor contributes to atrial fibrillation? Life Sci, 2021, 266: 118823.
14.	Luo B, Zheng R, Shi CQ, et al. DACT₂ modulates atrial fibrillation through TGF/β and Wnt signaling pathways. Heliyon, 2024, 10(16): e36050.
15.	Song ZP, Song HX, Liu D, et al. Overexpression of MFN2 alleviates sorafenib-induced cardiomyocyte necroptosis via the MAM-CaMKIIδ pathway in vitro and in vivo. Theranostics, 2022, 12(3): 1267-1285.
16.	Ploeg MC, Munts C, Prinzen FW, et al. Piezo1 mechanosensitive ion channel mediates stretch-induced Nppb expression in adult rat cardiac fibroblasts. Cell, 2021, 10(7): 1745.
17.	Jakob D, Klesen A, Allegrini B, et al. Piezo1 and BK_Ca channels in human atrial fibroblasts: interplay and remodelling in atrial fibrillation. J Mol Cell Cardiol, 2021, 158: 49-62.
18.	Frangogiannis NG. Transforming growth factor-β in myocardial disease. Nat Rev Cardiol. 2022, 19(7): 435-455.
19.	Lodyga M, Hinz B. TGF-β1: a truly transforming growth factor in fibrosis and immunity. Semin Cell Dev Biol, 2020, 101: 123-139.
20.	Chen J, Ye C, Wan C, et al. The roles of c-Jun N-Terminal kinase (JNK) in infectious diseases. Int J Mol Sci, 2021, 22(17): 9640.
21.	Plotnikov MB, Cherrnysheva GA, Smol'yakova VI, et al. Cardioprotective effects of a selective c-Jun N-terminal kinase inhibitor in a rat model of myocardial infarction. Biomedicines, 2023, 11(3): 714.
22.	Duan YL, Cheng SY, Jia L, et al. PDRPS7 protects cardiac cells from hypoxia/reoxygenation injury through inactivation of JNKs. FEBS Open Bio, 2020, 10(4): 593-606.
23.	Zhang Y, Yuan M, Cai WB, et al. Prostaglandin I₂ signaling prevents angiotensin Ⅱ-induced atrial remodeling and vulnerability to atrial fibrillation in mice. Cell Mol Life Sci, 2024, 81(1): 264.
24.	Shine M, Gordon J, Schärfen L, et al. Co-transcriptional gene regulation in eukaryotes and prokaryotes. Nat Rev Mol Cell Biol, 2024, 25(7): 534-554.
25.	Xie WJ, Liu M, Zhang X, et al. Astaxanthin suppresses LPS-induced myocardial apoptosis by regulating PTP1B/JNK pathway in vitro. Int Immunopharmacol, 2024, 127: 111395.
26.	Ibrahim KA, Abdelgaid HA, Eleyan M, et al. Resveratrol alleviates cardiac apoptosis following exposure to fenitrothion by modulating the sirtuin1/c-Jun N-terminal kinases/p53 pathway through pro-oxidant and inflammatory response improvements: in vivo and in silico studies. Life Sci, 2022, 290: 120265.
27.	Tkachenko A. Apoptosis and eryptosis: similarities and differences. Apoptosis, 2024, 29(3-4): 482-502.
28.	Newton K, Strasser A, Kayagaki N, et al. Cell death. Cell, 2024, 187(2): 235-256.
29.	Hu N, Sun M, Lv N, et al. ROS-suppression nanoplatform combined activation of STAT3/Bcl-2 pathway for preventing myocardial infarction in mice. ACS Appl Mater Interfaces, 2024, 16(10): 12188-12201.

1. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 2024, 149(1): e1-e156.
2. Chen LW, Li QZ, Chen JY, et al. A new procedure for elimination of atrial fibrillation associated with mitral valve disease: a proof-of-concept study. Int J Surg, 2023, 109(10): 2914-2925.
3. Chang C, Zhang CJ, Zhao X, et al. Differential regulation of mitogen-activated protein kinase signaling pathways in human with different types of mitral valvular disease. J Surg Res, 2013, 181(1): 49-59.
4. Qian YJ, Meng J, Tang H, et al. Different structural remodeling in atrial fibrillation with different types of mitral valvular diseases. Europace, 2010, 12(3): 371-377.
5. Beyer C, Tokarska L, Stühlinger M, et al. Structural cardiac remodeling in atrial fibrillation. JACC Cardiovasc Imaging, 2021, 14(11): 2199-2208.
6. Molnár AÁ, Sánta A, Pásztor DT, et al. Atrial cardiomyopathy in valvular heart disease: from molecular biology to clinical perspectives. Cells, 2023, 12(13): 1796.
7. Deng ZQ, Fan T, Xiao C, et al. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther, 2024, 9(1): 61.
8. Zhu EY, Liu Y, Zhong M, et al. Targeting NK-1R attenuates renal fibrosis via modulating inflammatory responses and cell fate in chronic kidney disease. Front Immunol, 2023, 14: 1142240.
9. Xie SY, Song SC, Liu SR, et al. (Pro)renin receptor mediates tubular epithelial cell pyroptosis in diabetic kidney disease via DPP4-JNK pathway. J Transl Med, 2024, 22(1): 26.
10. Gehi BR, Gadhave K, Uversky VN, et al. Intrinsic disorder in proteins associated with oxidative stress-induced JNK signaling. Cell Mol Life Sci, 2022, 79(4): 202.
11. Nadel G, Maik-Rachline G, Seger R. JNK cascade-induced apoptosis-a unique role in GqPCR signaling. Int J Mol Sci, 2023, 24(17): 13527.
12. Nikolic I, Leiva M, Sabio G. The role of stress kinases in metabolic disease. Nat Rev Endocrinol, 2020, 16(12): 697-716.
13. Babapoor-Farrokhran S, Tarighati Rasekhi R, Gill D, et al. How transforming growth factor contributes to atrial fibrillation? Life Sci, 2021, 266: 118823.
14. Luo B, Zheng R, Shi CQ, et al. DACT₂ modulates atrial fibrillation through TGF/β and Wnt signaling pathways. Heliyon, 2024, 10(16): e36050.
15. Song ZP, Song HX, Liu D, et al. Overexpression of MFN2 alleviates sorafenib-induced cardiomyocyte necroptosis via the MAM-CaMKIIδ pathway in vitro and in vivo. Theranostics, 2022, 12(3): 1267-1285.
16. Ploeg MC, Munts C, Prinzen FW, et al. Piezo1 mechanosensitive ion channel mediates stretch-induced Nppb expression in adult rat cardiac fibroblasts. Cell, 2021, 10(7): 1745.
17. Jakob D, Klesen A, Allegrini B, et al. Piezo1 and BK_Ca channels in human atrial fibroblasts: interplay and remodelling in atrial fibrillation. J Mol Cell Cardiol, 2021, 158: 49-62.
18. Frangogiannis NG. Transforming growth factor-β in myocardial disease. Nat Rev Cardiol. 2022, 19(7): 435-455.
19. Lodyga M, Hinz B. TGF-β1: a truly transforming growth factor in fibrosis and immunity. Semin Cell Dev Biol, 2020, 101: 123-139.
20. Chen J, Ye C, Wan C, et al. The roles of c-Jun N-Terminal kinase (JNK) in infectious diseases. Int J Mol Sci, 2021, 22(17): 9640.
21. Plotnikov MB, Cherrnysheva GA, Smol'yakova VI, et al. Cardioprotective effects of a selective c-Jun N-terminal kinase inhibitor in a rat model of myocardial infarction. Biomedicines, 2023, 11(3): 714.
22. Duan YL, Cheng SY, Jia L, et al. PDRPS7 protects cardiac cells from hypoxia/reoxygenation injury through inactivation of JNKs. FEBS Open Bio, 2020, 10(4): 593-606.
23. Zhang Y, Yuan M, Cai WB, et al. Prostaglandin I₂ signaling prevents angiotensin Ⅱ-induced atrial remodeling and vulnerability to atrial fibrillation in mice. Cell Mol Life Sci, 2024, 81(1): 264.
24. Shine M, Gordon J, Schärfen L, et al. Co-transcriptional gene regulation in eukaryotes and prokaryotes. Nat Rev Mol Cell Biol, 2024, 25(7): 534-554.
25. Xie WJ, Liu M, Zhang X, et al. Astaxanthin suppresses LPS-induced myocardial apoptosis by regulating PTP1B/JNK pathway in vitro. Int Immunopharmacol, 2024, 127: 111395.
26. Ibrahim KA, Abdelgaid HA, Eleyan M, et al. Resveratrol alleviates cardiac apoptosis following exposure to fenitrothion by modulating the sirtuin1/c-Jun N-terminal kinases/p53 pathway through pro-oxidant and inflammatory response improvements: in vivo and in silico studies. Life Sci, 2022, 290: 120265.
27. Tkachenko A. Apoptosis and eryptosis: similarities and differences. Apoptosis, 2024, 29(3-4): 482-502.
28. Newton K, Strasser A, Kayagaki N, et al. Cell death. Cell, 2024, 187(2): 235-256.
29. Hu N, Sun M, Lv N, et al. ROS-suppression nanoplatform combined activation of STAT3/Bcl-2 pathway for preventing myocardial infarction in mice. ACS Appl Mater Interfaces, 2024, 16(10): 12188-12201.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Latest ArticlesRegulation of TGF-β1/JNK signaling pathway in patients with different types of mitral valve diseases complicated by atrial fibrillation

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