Mechanical stresses induce paracrine ß-2 microglobulin from cardiomyocytes to activate cardiac fibroblasts through epidermal growth factor receptor.
Clin Sci (Lond)
; 132(16): 1855-1874, 2018 08 31.
Article
em En
| MEDLINE
| ID: mdl-30072448
ABSTRACT
By employing a proteomic analysis on supernatant of mechanically stretched cardiomyocytes, we found that stretch induced a significantly high level of ß-2 microglobulin (ß2M), a non-glycosylated protein, which is related to inflammatory diseases but rarely known in cardiovascular diseases. The present data showed that serum ß2M 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 ß2M level correlated to cardiac dysfunction in these patients. In pressure overload mice model by transverse aortic constriction (TAC), ß2M levels in serum and heart tissue increased progressively in a time-dependent manner. Exogenous ß2M showed pro-fibrotic effects in cultured cardiac fibroblasts but few effects in cardiomyocytes. Adeno-associated virus 9 (AAV9)-mediated knockdown of ß2M significantly reduced cardiac ß2M 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 ß2M 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 ß2M-knockdown cardiomyocytes. In vivo, knockdown of ß2M inhibited the increase in phosphorylation of epidermal growth factor receptor (EGFR) induced by TAC. In cultured cardiac fibroblasts, inhibition of EGFR significantly attenuated the ß2M-induced the activation of EGFR and pro-fibrotic responses. The present study suggests that ß2M is a paracrine pro-fibrotic mediator and associated with cardiac dysfunction in response to pressure overload.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estresse Mecânico
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Microglobulina beta-2
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Miócitos Cardíacos
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Fibroblastos
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Receptores ErbB
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Hipertensão
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Animals
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article