By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of β-2 microglobulin (β2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum β2M level was increased in patients with hypertension and further increased in patients with chronic heart failure (HF) as compared with control group, and the high level of serum β2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), β2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous β2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of β2M significantly reduced cardiac β2M level and inhibited myocardial fibrosis and cardiac dysfunction but not cardiac hypertrophy at 4 weeks after TAC. In vitro, mechanical stretch induced the rapid secretion of β2M mainly from cardiomyocytes by activation of extracellular-regulated protein kinase (ERK). Conditional medium (CM) from mechanically stretched cardiomyocytes activated cultured cardiac fibroblasts, and the effect was partly abolished by CM from β2M-knockdown cardiomyocytes. In vivo, knockdown of β2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the β2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that β2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.
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A depiction of the mechanism of cellular autophagy showing the fusion of a lysosome with an autophagosome. The various molecules involved in the process can be seen alongside different microbes within the autophagosome. In this issue of Clinical Science, Li et al. (issue 15, pages 1645–1667) investigate the role of HMGB1-induced autophagy in liver fibrosis, and Andrade-Silva et al. (issue 16, pages 1725–1739) discuss the involvement of TLR2 and TLR4 in autophagy associated with cisplatin-induced acute kidney injury.
Research Article|
August 30 2018
Mechanical stresses induce paracrine β-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor
Yang Li;
Yang Li
*
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Xiaoyi Zhang;
Xiaoyi Zhang
*
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
2Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Lu Li;
Lu Li
*
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
3Department of Rehabilitation Medicine, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200127, China
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Xiang Wang;
Xiang Wang
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Zhidan Chen;
Zhidan Chen
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Xingxu Wang;
Xingxu Wang
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Ying Wang;
Ying Wang
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Le Kang;
Le Kang
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Yong Ye;
Yong Ye
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Jianguo Jia;
Jianguo Jia
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Guoping Zhang;
Guoping Zhang
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Chunjie Yang;
Chunjie Yang
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Jie Yuan;
Jie Yuan
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Jingmin Zhou;
Jingmin Zhou
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Junbo Ge;
Junbo Ge
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Hui Gong;
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
Correspondence: Hui Gong ([email protected]) and Yunzeng Zou ([email protected])
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Yunzeng Zou
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
Correspondence: Hui Gong ([email protected]) and Yunzeng Zou ([email protected])
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Publisher: Portland Press Ltd
Received:
June 11 2018
Revision Received:
July 31 2018
Accepted:
August 02 2018
Accepted Manuscript online:
August 02 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (16): 1855–1874.
Article history
Received:
June 11 2018
Revision Received:
July 31 2018
Accepted:
August 02 2018
Accepted Manuscript online:
August 02 2018
Connected Content
A commentary has been published:
Novel role for cardiac myocyte-derived β-2 microglobulin in mediating cardiac fibrosis
Citation
Yang Li, Xiaoyi Zhang, Lu Li, Xiang Wang, Zhidan Chen, Xingxu Wang, Ying Wang, Le Kang, Yong Ye, Jianguo Jia, Guoping Zhang, Chunjie Yang, Jie Yuan, Jingmin Zhou, Junbo Ge, Hui Gong, Yunzeng Zou; Mechanical stresses induce paracrine β-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor. Clin Sci (Lond) 31 August 2018; 132 (16): 1855–1874. doi: https://doi.org/10.1042/CS20180486
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