Action mechanism of microRNA-484 involved in myocardial fibrosis in hypertrophic cardiomyopathy_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HUANG Derong ¹ , CHEN Zhongxiu ² , CHEN Hongying ³ , CHEN Xuemei ³ ,  DIAN Ke ⁴

1. Department of Cardiovascular Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, P. R. China;
2. Department of Cardiology, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China;
3. Cell and Molecular Biology Laboratory, Life Science Park, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China;
4. Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China;

Corresponding author：

DIAN Ke, Email: 18798105417@163.com

Keywords：

Hypertrophic cardiomyopathy; myocardial fibrosis; microRNAs

DOI：

10.7507/1007-4848.202203039

Video：

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Objective To search for the key microRNAs (miRNAs) involved in myocardial fibrosis in hypertrophic cardiomyopathy, and to further explore the mechanisms involved in the regulation of myocardial fibrosis. Methods Forty-two patients with hypertrophic cardiomyopathy diagnosed and treated surgically in West China Hospital of Sichuan University from January 2014 to June 2018 were selected, including 29 males and 13 females, with a median age of 46 (15-69) years. In the myocardial tissue of patients with hypertrophic cardiomyopathy with different degrees of fibrosis, miRNAs with significantly different expression were screened and further verified at the cellular level. By regulating the expression of the target miRNAs, the expressions of fibrosis-related proteins and target genes were detected respectively. Finally, the target-binding relationship was verified by dual-luciferase reporter gene detection. Results miR-484 was up-regulated in severely fibrotic myocardial tissue and activated cardiac fibroblasts. After cardiac fibroblasts were activated by TGF-β1, the expression of miR-484 was significantly up-regulated, the expression of fibrosis-related proteins (CollagenⅠ, α-SMA) increased, and the expression of the target gene HIPK1 decreased (P<0.05). After inhibiting the expression of miR-484 by transfection of miR-484 antagomir, the expression of fibrosis-related proteins decreased, while expression of HIPK1 was up-regulated (P<0.05). The detection of dual luciferase reporter gene showed that the luciferase activity of the transfected WT-miRNA-484 mimics group was lower than that of the control group (P<0.05). Conclusion miR-484 is a pro-fibrotic miRNA that participates in the process of myocardial fibrosis by negatively regulating the expression of HIPK1. It can be used as a regulatory target to provide a therapeutic strategy for myocardial fibrosis.

Citation： HUANG Derong, CHEN Zhongxiu, CHEN Hongying, CHEN Xuemei, DIAN Ke. Action mechanism of microRNA-484 involved in myocardial fibrosis in hypertrophic cardiomyopathy. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(9): 1316-1322. doi: 10.7507/1007-4848.202203039 Copy

1.	Bi X, Yang C, Song Y, et al. Quantitative fragmented QRS has a good diagnostic value on myocardial fibrosis in hypertrophic obstructive cardiomyopathy based on clinical-pathological study. BMC Cardiovasc Disord, 2020, 20(1): 298.
2.	Raman B, Ariga R, Spartera M, et al. Progression of myocardial fibrosis in hypertrophic cardiomyopathy: Mechanisms and clinical implications. Eur Heart J Cardiovasc Imaging, 2019, 20(2): 157-167.
3.	Melacini P, Basso C, Angelini A, et al. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J, 2010, 31(17): 2111-2123.
4.	张艳, 吴昆华, 李清, 等. 肥厚型心肌病患者心肌纤维化范围的相关因素分析. 中华心血管病杂志, 2021, 49(1): 31-36.
5.	Olivotto I, Maron BJ, Appelbaum E, et al. Spectrum and clinical significance of systolic function and myocardial fibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Am J Cardiol, 2010, 106(2): 261-267.
6.	张沫, 孙筱璐, 吴桂鑫, 等. 不同类型的非梗阻性肥厚型心肌病患者的临床及遗传学特征. 中华心血管病杂志, 2021, 49(6): 593-600.
7.	Huang L, Ran L, Zhao P, et al. MRI native T1 and T2 mapping of myocardial segments in hypertrophic cardiomyopathy: Tissue remodeling manifested prior to structure changes. Br J Radiol, 2019, 92(1104): 20190634.
8.	周颖, 袁建松, 陈游洲, 等. Apelin通过TGF β-smads信号通路抑制肥厚型心肌病转基因小鼠心肌纤维化. 中华心力衰竭和心肌病杂志, 2017, 1(1): 32-39.
9.	Olson EN. MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med, 2014, 6(239): 239ps3.
10.	Bittencourt MI, Cader SA, Araújo DV, et al. Role of myocardial fibrosis in hypertrophic cardiomyopathy: A systematic review and updated meta-analysis of risk markers for sudden death. Arq Bras Cardiol, 2019, 112(3): 281-289.
11.	陈凤梅, 鲁星琴, 姚亚丽. 主动脉弹性与肥厚型心肌病及其心肌纤维化的关系. 国际心血管病杂志, 2020, 47(4): 207-210.
12.	Moravsky G, Ofek E, Rakowski H, et al. Myocardial fibrosis in hypertrophic cardiomyopathy: Accurate reflection of histopathological findings by CMR. JACC Cardiovasc Imaging, 2013, 6(5): 587-596.
13.	Gyöngyösi M, Winkler J, Ramos I, et al. Myocardial fibrosis: Biomedical research from bench to bedside. Eur J Heart Fail, 2017, 19(2): 177-191.
14.	Nguyen MN, Kiriazis H, Gao XM, et al. Cardiac fibrosis and arrhythmogenesis. Compr Physiol, 2017, 7(3): 1009-1049.
15.	Stempien-Otero A, Kim DH, Davis J. Molecular networks underlying myofibroblast fate and fibrosis. J Mol Cell Cardiol, 2016, 97: 153-161.
16.	Travers JG, Kamal FA, Robbins J, et al. Cardiac fibrosis: The fibroblast awakens. Circ Res, 2016, 118(6): 1021-1040.
17.	史承勇, 王波, 郭显, 等. 鞘鞍醇激酶-2在转化生长因子-β1诱导心脏成纤维细胞增殖与活化过程中作用. 临床军医杂志, 2019, 47(5): 525-528, 531.
18.	张利芬, 李彬彬, 余宏宇. MicroRNA-484通过靶向肝星状细胞中Fis1调控肝纤维化进程. 第二军医大学学报, 2017, 38(9): 1146-1151.
19.	黄秀, 张洋洋, 朱晓宇, 等. TGF-β1/Smads信号通路及其与肾脏纤维化关系的研究进展. 山东医药, 2019, 59(21): 103-107.
20.	Inwood S, Buehler E, Betenbaugh M, et al. Identifying HIPK1 as target of miR-22-3p enhancing recombinant protein production from HEK 293 cell by using microarray and HTP siRNA screen. Biotechnol J. 2018, 13: 1-17.
21.	Hong Y, Cao H, Wang Q, et al. MiR-22 may suppress fibrogenesis by targeting TGFβR I in cardiac fibroblasts. Cell Physiol Biochem, 2016, 40(6): 1345-1353.

1. Bi X, Yang C, Song Y, et al. Quantitative fragmented QRS has a good diagnostic value on myocardial fibrosis in hypertrophic obstructive cardiomyopathy based on clinical-pathological study. BMC Cardiovasc Disord, 2020, 20(1): 298.
2. Raman B, Ariga R, Spartera M, et al. Progression of myocardial fibrosis in hypertrophic cardiomyopathy: Mechanisms and clinical implications. Eur Heart J Cardiovasc Imaging, 2019, 20(2): 157-167.
3. Melacini P, Basso C, Angelini A, et al. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J, 2010, 31(17): 2111-2123.
4. 张艳, 吴昆华, 李清, 等. 肥厚型心肌病患者心肌纤维化范围的相关因素分析. 中华心血管病杂志, 2021, 49(1): 31-36.
5. Olivotto I, Maron BJ, Appelbaum E, et al. Spectrum and clinical significance of systolic function and myocardial fibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Am J Cardiol, 2010, 106(2): 261-267.
6. 张沫, 孙筱璐, 吴桂鑫, 等. 不同类型的非梗阻性肥厚型心肌病患者的临床及遗传学特征. 中华心血管病杂志, 2021, 49(6): 593-600.
7. Huang L, Ran L, Zhao P, et al. MRI native T1 and T2 mapping of myocardial segments in hypertrophic cardiomyopathy: Tissue remodeling manifested prior to structure changes. Br J Radiol, 2019, 92(1104): 20190634.
8. 周颖, 袁建松, 陈游洲, 等. Apelin通过TGF β-smads信号通路抑制肥厚型心肌病转基因小鼠心肌纤维化. 中华心力衰竭和心肌病杂志, 2017, 1(1): 32-39.
9. Olson EN. MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med, 2014, 6(239): 239ps3.
10. Bittencourt MI, Cader SA, Araújo DV, et al. Role of myocardial fibrosis in hypertrophic cardiomyopathy: A systematic review and updated meta-analysis of risk markers for sudden death. Arq Bras Cardiol, 2019, 112(3): 281-289.
11. 陈凤梅, 鲁星琴, 姚亚丽. 主动脉弹性与肥厚型心肌病及其心肌纤维化的关系. 国际心血管病杂志, 2020, 47(4): 207-210.
12. Moravsky G, Ofek E, Rakowski H, et al. Myocardial fibrosis in hypertrophic cardiomyopathy: Accurate reflection of histopathological findings by CMR. JACC Cardiovasc Imaging, 2013, 6(5): 587-596.
13. Gyöngyösi M, Winkler J, Ramos I, et al. Myocardial fibrosis: Biomedical research from bench to bedside. Eur J Heart Fail, 2017, 19(2): 177-191.
14. Nguyen MN, Kiriazis H, Gao XM, et al. Cardiac fibrosis and arrhythmogenesis. Compr Physiol, 2017, 7(3): 1009-1049.
15. Stempien-Otero A, Kim DH, Davis J. Molecular networks underlying myofibroblast fate and fibrosis. J Mol Cell Cardiol, 2016, 97: 153-161.
16. Travers JG, Kamal FA, Robbins J, et al. Cardiac fibrosis: The fibroblast awakens. Circ Res, 2016, 118(6): 1021-1040.
17. 史承勇, 王波, 郭显, 等. 鞘鞍醇激酶-2在转化生长因子-β1诱导心脏成纤维细胞增殖与活化过程中作用. 临床军医杂志, 2019, 47(5): 525-528, 531.
18. 张利芬, 李彬彬, 余宏宇. MicroRNA-484通过靶向肝星状细胞中Fis1调控肝纤维化进程. 第二军医大学学报, 2017, 38(9): 1146-1151.
19. 黄秀, 张洋洋, 朱晓宇, 等. TGF-β1/Smads信号通路及其与肾脏纤维化关系的研究进展. 山东医药, 2019, 59(21): 103-107.
20. Inwood S, Buehler E, Betenbaugh M, et al. Identifying HIPK1 as target of miR-22-3p enhancing recombinant protein production from HEK 293 cell by using microarray and HTP siRNA screen. Biotechnol J. 2018, 13: 1-17.
21. Hong Y, Cao H, Wang Q, et al. MiR-22 may suppress fibrogenesis by targeting TGFβR I in cardiac fibroblasts. Cell Physiol Biochem, 2016, 40(6): 1345-1353.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Action mechanism of microRNA-484 involved in myocardial fibrosis in hypertrophic cardiomyopathy

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