Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease.
Clin Sci (Lond)
; 133(22): 2283-2299, 2019 11 29.
Article
em En
| MEDLINE
| ID: mdl-31713591
ABSTRACT
The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)-/- mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with FcÉ£ receptor I (FcÉ£RI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE-/- mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcÉ£R1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
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Tratamento
Base de dados:
MEDLINE
Assunto principal:
Doença da Artéria Coronariana
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Receptores Imunológicos
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Receptores de IgG
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Sistema de Sinalização das MAP Quinases
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Macrófagos
Tipo de estudo:
Observational_studies
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Risk_factors_studies
Limite:
Adult
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Animals
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Humans
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Middle aged
Idioma:
En
Revista:
Clin Sci (Lond)
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Índia