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Calcification induced by type I Interferon in human aortic valve interstitial cells is larger in males and blunted by a Janus kinase inhibitor

AuthorsParra Izquierdo, Iván; Castaños-Mollor, Irene; López, Javier ; Gómez, Cristina ; San Román, José Alberto; Sánchez Crespo, Mariano; García-Rodríguez, Carmen
KeywordsAortic valve
Cell survival
Issue Date2018
PublisherAmerican Heart Association
CitationArteriosclerosis, Thrombosis, and Vascular Biology 38(9): 2148-2159 (2018)
Abstract[Objective] Calcific aortic valve disease is the most prevalent valvulopathy in Western countries. An unanticipated pathogenetic clue involving IFN (interferon) was disclosed by the finding of constitutive type I IFN activity associated with aortic valve calcification in children with the atypical Singleton-Merten syndrome. On this basis, the role of type I IFN on inflammation and calcification in human aortic valve interstitial cells (AVIC) was examined.
[Approach and Results] IFN-α was weakly proinflammatory but potentiated lipopolysaccharide-mediated activation of NF (nuclear factor)-κB and the ensuing induction of proinflammatory molecules in human AVIC. Stimulation with IFN-α and in combination with lipopolysaccharide promoted osteoblast-like differentiation characterized by increased osteoblastic gene expression, BMP (bone morphogenetic protein)-2 secretion, and ectopic phosphatase activity. Sex differences were observed. Likewise, IFN-α treatment of human AVICs in osteogenic medium resulted in increased formation of calcific nodules. Strikingly, IFN-α–mediated calcification was significantly higher in AVICs from males, and was blocked by tofacitinib, a JAK (Janus kinase) inhibitor, and by a BMP antagonist. A female-specific protective mechanism involving the activation of PI3K-Akt (protein kinase B) pathways and cell survival was disclosed. Females exhibited higher levels of BCL2 in valve cells and tissues and lower annexin V staining on cell stimulation.
[Conclusions] IFN-α acts as a proinflammatory and pro-osteogenic cytokine in AVICs, its effects being potentiated by lipopolysaccharide. Results also uncovered sex differences with lower responses in female AVICs and sex-specific mechanisms involving apoptosis. Data point to JAK/STAT (signal transducer and activator of transcription) system as a potential therapeutic target for calcific aortic valve disease.
Publisher version (URL)https://doi.org/10.1161/ATVBAHA.118.311504
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