PMID- 30072448 OWN - NLM STAT- MEDLINE DCOM- 20190826 LR - 20190826 IS - 1470-8736 (Electronic) IS - 0143-5221 (Linking) VI - 132 IP - 16 DP - 2018 Aug 31 TI - Mechanical stresses induce paracrine beta-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor. PG - 1855-1874 LID - 10.1042/CS20180486 [doi] AB - By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of beta-2 microglobulin (beta2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum beta2M 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 beta2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), beta2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous beta2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of beta2M significantly reduced cardiac beta2M 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 beta2M 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 beta2M-knockdown cardiomyocytes. In vivo, knockdown of beta2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the beta2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that beta2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload. CI - (c) 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society. FAU - Li, Yang AU - Li Y AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Zhang, Xiaoyi AU - Zhang X AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. AD - Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai 200032, China. FAU - Li, Lu AU - Li L AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. AD - Department of Rehabilitation Medicine, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200127, China. FAU - Wang, Xiang AU - Wang X AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Chen, Zhidan AU - Chen Z AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Wang, Xingxu AU - Wang X AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Wang, Ying AU - Wang Y AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Kang, Le AU - Kang L AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Ye, Yong AU - Ye Y AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Jia, Jianguo AU - Jia J AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Zhang, Guoping AU - Zhang G AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Yang, Chunjie AU - Yang C AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Yuan, Jie AU - Yuan J AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Zhou, Jingmin AU - Zhou J AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Ge, Junbo AU - Ge J AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. FAU - Gong, Hui AU - Gong H AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China gonghui2005@fudan.edu.cn zou.yunzeng@zs-hospital.sh.cn. FAU - Zou, Yunzeng AU - Zou Y AD - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China gonghui2005@fudan.edu.cn zou.yunzeng@zs-hospital.sh.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180830 PL - England TA - Clin Sci (Lond) JT - Clinical science (London, England : 1979) JID - 7905731 RN - 0 (Culture Media, Conditioned) RN - 0 (beta 2-Microglobulin) RN - EC 2.7.10.1 (ErbB Receptors) CIN - Clin Sci (Lond). 2018 Oct 5;132(19):2117-2120. PMID: 30291210 MH - Adult MH - Aged MH - Animals MH - Cells, Cultured MH - Culture Media, Conditioned/pharmacology MH - ErbB Receptors/genetics/*metabolism MH - Fibroblasts/drug effects/*metabolism MH - Humans MH - Hypertension/blood/*metabolism/physiopathology MH - Male MH - Mice, Inbred C57BL MH - Middle Aged MH - Myocytes, Cardiac/drug effects/*metabolism MH - Paracrine Communication/drug effects MH - RNA Interference MH - Rats, Sprague-Dawley MH - *Stress, Mechanical MH - beta 2-Microglobulin/blood/genetics/*metabolism OTO - NOTNLM OT - Beta-2 microglobulin OT - Cardiac fibroblast OT - Fibrosis OT - Hypertension OT - Mechanical stress OT - cardiomyocytes EDAT- 2018/08/04 06:00 MHDA- 2019/08/27 06:00 CRDT- 2018/08/04 06:00 PHST- 2018/06/11 00:00 [received] PHST- 2018/07/31 00:00 [revised] PHST- 2018/08/02 00:00 [accepted] PHST- 2018/08/04 06:00 [pubmed] PHST- 2019/08/27 06:00 [medline] PHST- 2018/08/04 06:00 [entrez] AID - CS20180486 [pii] AID - 10.1042/CS20180486 [doi] PST - epublish SO - Clin Sci (Lond). 2018 Aug 30;132(16):1855-1874. doi: 10.1042/CS20180486. Print 2018 Aug 31.