P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease.
J Mol Cell Cardiol
; 72: 146-56, 2014 Jul.
Article
em En
| MEDLINE
| ID: mdl-24631773
ABSTRACT
Calcific aortic valve disease (CAVD) is a disorder characterized by an abnormal mineralization, which may have intricate links with inflammation. Interleukin-6 (IL-6) and its cognate cytokines are widely expressed and exert pleiotropic effects on different tissues. In this study, we examined the expression of the IL-6 family of cytokines in human CAVD by using a transcriptomic approach and we performed in-depth functional assays with valve interstitial cells (VICs) to unravel the process regulating IL-6 expression and its role during the mineralization of the aortic valve. We documented by both microarray and q-PCR analyses an elevated expression of IL-6 in human CAVD, which was correlated with the remodeling process. IL-6 was highly expressed by VICs. We found that following treatment with a phosphate-containing medium the level of IL-6 expressed by VICs increased by several-fold. Phosphate-induced expression of IL-6 relied on reduced PI3K/Akt signaling downstream of the P2Y2 receptor (P2Y2R). In this regard, we found by using transfection experiments that Akt-1 is a negative regulator of the NF-κB pathway. In addition, by using a siRNA targeting IL-6 we found that phosphate-induced mineralization was largely dependent on IL-6 expression. A transfection of Akt-1 rescued the hypermineralizing phenotype of P2Y2R(-/-) mouse VICS (MVICs). Hence, we documented a novel mechanism whereby P2Y2R and Akt modulate the NF-κB pathway and its downstream target IL-6, which is a strong promoter of the mineralization of VICs.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Valva Aórtica
/
Estenose da Valva Aórtica
/
Fosfatos
/
Calcinose
/
Interleucina-6
/
Proteínas Proto-Oncogênicas c-akt
/
Receptores Purinérgicos P2Y2
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Canadá