P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt : implication for calcific aortic valve disease
|Authors:||El Husseini, Diala; Boulanger, Marie-Chloé; Mahmut, Ablajan; Bouchareb, Rihab; Laflamme, Marie-Hélène; Fournier, Dominique; Pibarot, Philippe; Bossé, Yohan; Mathieu, Patrick|
|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-¿B 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-¿B pathway and its downstream target IL-6, which is a strong promoter of the mineralization of VICs|
|Document Type:||Article de recherche|
|Issue Date:||11 March 2014|
|Open Access Date:||Restricted access|
|This document was published in:||Journal of molecular and cellular cardiology, Vol. 72, 146–156 (2014)|
Academic Press Inc, Ltd.
|Collection:||Articles publiés dans des revues avec comité de lecture|
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